The present invention comprises a new class of compounds useful in treating diseases, such as TNF-xcex1, IL-1xcex2, IL-6 and/or IL-8 mediated diseases and other maladies, such as pain and diabetes. In particular, the compounds of the invention are useful for the prophylaxis and treatment of diseases or conditions involving inflammation. This invention, in particular, relates to novel aryl and heteroaryl substituted fused pyrrole compounds, compositions containing such compounds and methods of use of such compounds. The subject invention also relates to processes for making such compounds as well as to intermediates useful in such processes.
Interleukin-1 (IL-1) and Tumor Necrosis Factor alpha (TNF-a) are proinflammatory cytokines secreted by a variety of cells including monocytes and macrophages in response to many inflammatory stimuli (e.g. lipopolysaccharidexe2x80x94LPS) or external cellular stress (e.g. osmotic shock, peroxide). Elevated levels of TNF-xcex1 and/or IL-1 over basal levels have been implicated in mediating or exacerbating a number of disease states including rheumatoid arthritis; Pagets disease; osteophorosis; multiple myeloma; uveititis; acute and chronic myelogenous leukemia; pancreatic xcex2 cell destruction; osteoarthritis; rheumatoid spondylitis; gouty arthritis; inflammatory bowel disease; adult respiratory distress syndrome (ARDS); psoriasis; Crohn""s disease; allergic rhinitis; ulcerative colitis; anaphylaxis; contact dermatitis; asthma; muscle degeneration; cachexia; Reiter""s syndrome; type I and type II diabetes; bone resorption diseases; graft vs. host reaction; ischemia reperfusion injury; atherosclerosis; brain trauma; multiple sclerosis; cerebral malaria; sepsis; septic shock; toxic shock syndrome; fever, and myalgias due to infection. HIV-1, HIV-2, HIV-3, cytomegalovirus (CMV), influenza, adenovirus, the herpes viruses (including HSV-1, HSV-2), and herpes zoster are also exacerbated by TNF-xcex1.
Elevated levels of IL-1 over basal levels have been implicated in mediating or exacerbating a number of disease states including rheumatoid arthritis; osteoarthritis; rheumatoid spondylitis; gouty arthritis; inflammatory bowel disease; adult respiratory distress syndrome (ARDS); psoriasis; Crohn""s disease; ulcerative colitis; anaphylaxis; muscle degeneration; cachexia; Reiter""s syndrome; type I and type II diabetes; bone resorption diseases; ischemia reperfusion injury; atherosclerosis; brain trauma; multiple sclerosis; sepsis; septic shock; and toxic shock syndrome. Viruses sensitive to TNF-xcex1 inhibition, e.g., HIV-1, HIV-2, HIV-3, are also affected by IL-1.
TNF-xcex1 and IL-1 appear to play a role in pancreatic xcex2 cell destruction and diabetes. Pancreatic xcex2 cells produce insulin which helps mediate blood glucose homeostasis. Deterioration of pancreatic xcex2 cells often accompanies type I diabetes. Pancreatic xcex2 cell functional abnormalities may occur inpatients with type II diabetes. Type II diabetes is characterized by a functional resistance to insulin. Further, type II diabetes is also often accompanied by elevated levels of plasma glucagon and increased rates of hepatic glucose production. Glucagon is a regulatory hormone that attenuates liver gluconeogenesis inhibition by insulin. Glucagon receptors have been found in the liver, kidney and adipose tissue. Thus glucagon antagonists are useful for attenuating plasma glucose levels (WO 97/16442, incorporated herein by reference in its entirety). By antagonizing the glucagon receptors, it is thought that insulin responsiveness in the liver will improve, thereby decreasing gluconeogenesis and lowering the rate of hepatic glucose production.
Several approaches have been taken to block the effects of TNF-a. One approach involves utilizing soluble receptors for TNF-a (e.g., TNFR-55 or TNFR-75) which have demonstrated efficacy in animal models of TNF-a mediated disease states (for a PEG dimer of TNFR-55 see Edwards CHI Meeting Nov. 13-15 (1995) and rhu sTNFR:Fc p-75 see Moreland). A second approach to neutralizing TNF-a utilizing a monoclonal antibody specific to TNF-a, cA2, has demonstrated improvement in swollen joint count in a Phase II human trial of rheumatoid arthritis (Feldmann et al Immunological Reviews p.195-223 (1995)).
The above approaches block the effects of TNF-a and IL-1 by either protein sequesterazation or receptor antagonism, but an additional approach to blockade is to intervene in the cellular production and secretion of IL-1 and/or TNF. There are numerous points for intervention between the extracellular stimulus and the secretion of IL-1 and TNF-a from the cell including interfering with transcriptional processes, interfering with translational processes, blocking signal transduction which may alter protein translation and/or transcription; and blocking release of the proteins from the cells. The most reliable effect to document is upon applying a given stimulus to a cell in vitro (eg. monocyte), a certain amount of TNF or IL-1 (note: quantitated by enzyme linked immunoabsorbent assay, ELISA) is secreted over basal levels in the culture medium. Evidence as to the nature of intervention between the extracellular stimulus and the secretion of IL-1 and TNF-a from the cell can be provided by in vitro biochemical experiments, but it does not preclude the fact that the compounds may be intervening at a yet undetermined point on the pathway between extracellular stimulus and secretion of protein. Pentoxifylline is an example of a compound that is believed to intervene at the transcriptional level of IL-1 protein synthesis. Evidence suggests that the antiinflammatory glucocorticoids block at both the transcriptional and translational levels (Lee et al Circulatory Shock 44:97-103 (1995)) of inflammatory mediators. Chloroquine (CQ) and hydroxychloroquine (HCQ) accumulate in lysosomes of monocytes (Borne Handbook of Cardiovascular and Anti-Inflammatory Agents p27-104 (1986)). CQ and HCQ inhibit cartilage cathepsin B and cartilage chondromucoprotease, and they may have membrane stabilizing effects on the lysozomes.
Since TNF-a is upstream in the cytokine cascade of inflammation wherein elevated levels of TNF-a lead to elevated levels. of other cytokines including IL-1, IL-6 and IL-8, inhibiting the production of TNF-a may also reduce levels of other cytokines including but not limited to IL-1, IL-6 or IL-8. IL-8 is implicated in exacerbating and/or causing many disease states in which massive neutrophil infiltration into sites of inflammation or injury (e.g., ischemia) is mediated by the chemotactic nature of IL-8 including but not limited to the following: asthma, inflammatory bowel disease, psoriasis, adult respiratory distress syndrome, cardiac and renal reperfusion injury, thrombosis and glomerulonephritis. In addition to the chemotaxis effect on neutrophils, IL-8 also has the ability to activate neutrophils. Thus, reduction in IL-8 levels would lead to diminished neutrophil infiltration. Evidence has been reported that suggests P-38 plays a role in TNF induced transcriptional activation of IL-6 production (see: Walter Fiers EMBO Journal 1996, vol. 15, p 1914-23) and of IL-8 production (Dinarello, Proc. Nat. Acad. Sci. 1995 Vol 92, 12230-4).
In rheumatoid arthritis, both IL-1 and TNF-a induce synoviocytes and chondrocytes to produce collagenase and neutral proteases which leads to tissue destruction within the arthritic joints. In a model of arthritis, collagen-induced arthritis (CIA) in rats and mice, intraarticular administration of TNF-a either prior to or after the induction of CIA led to an accelerated onset of arthritis and a more severe course of the disease (Brahn et al Lymphokine Cytokine Res. (11):253-256, (1992); and Cooper Clin. Exp. Immunol. 898:244-250, (1992)).
It has been reported that TNF-a plays a role in head trauma, stroke, and ischemia. For instance, in animal models of head trauma (rat), TNF-a levels increased in the contused hemisphere (Shohami et al J. Cereb. Blood Flow Metab. 14:615-619 (1994)). In an model of ischemia wherein the middle cerebral artery was occluded in rats, the levels of mRNA of TNF-a increased (Feurstein et al Neurosci. Lett. 164: 125-128 (1993)). Administration of TNF-a into the rat cortex resulted in significant PMN accumulation in capillaries and adherance in small blood vessels. The TNF-a promotes the infiltration of other cytokines (IL-1b, IL-6), and also chemokines, which promote neutrophil infiltration into the infarct area (Feurstein Stroke 25:1481-1488 (1994)).
TNF-a may play a role in promoting certain viral life cycles and disease states associated with them. For instance, TNF-a secreted by monocytes induced elevated levels of HIV expression in a chronically infected T cell clone (Clouse et al, J. Immunol. 142: 431 (1989)). The role of TNF-a in the HIV associated states of cachexia and muscle degradation has been discussed (Lahdevirta et al The American J. Med. 85:289 (1988)).
Elevated levels of IL-1 over basal levels have been implicated in mediating or exacerbating a number of disease states including rheumatoid arthritis; osteoarthritis; rheumatoid spondylitis; gouty arthritis; inflammatory bowel disease; adult respiratory distress syndrome (ARDS); psoriasis; Crohn""s disease; ulcerative colitis; anaphylaxis; muscle degeneration; antiviral therapy including those viruses sensitive to TNF-a inhibitionxe2x80x94HIV-1, HIV-2, HIV-3; cachexia; Reiter""s syndrome; type II diabetes; bone resorption diseases; ischemia reperfusion injury; atherosclerosis; brain trauma; multiple sclerosis; sepsis; septic shock; and toxic shock syndrome.
In rheumatoid arthritis models in animals, multiple intraarticular injections of IL-1 have lead to an acute and destructive form of arthritis (Chandrasekhar et al Clinical Immunol Immunopathol. 55:382-400 (1990)). In studies using cultured rheumatoid synovial cells, IL-1 is a more potent inducer of stromelysin than is TNF-a (Firestein Am. J. Pathol. 140:1309-1314, (1992)). At sites of local injection, neutrophil, lymphocyte, and monocyte emigration occurs. The emigration is attributed to the induction of chemokines (i.e. IL-8), and the up regulation of adhesion molecules (Dinarello Eur. Cytokine Netw. 5:517-531 (1994)).
IL-1 does play a role in promoting certain viral life cycles. Cytokine-induced increase of HIV expression in a chronically infected macrophage line has been associated with the concomittant and selective increase of IL-1 production (Folks et al J. Immunol. 136:40-49, (1986)). The role of IL-1 in cachexia has been discussed (Beutler et al J. Immunol. 135:3969-3971 (1985)). The role of IL-1 in muscle degeneration has been discussed (Baracos et al N. Eng. J. Med. 308:553-558 (1983)).
IL-8 has been implicated in exacerbating and/or causing many disease states in which massive neutrophil infiltration into sites of inflammation or injury (eg ischemia) is mediated by the chemotactic nature of IL-8 including but not limited to the following: asthma, inflammatory bowel disease, psoriasis, adult respiratory distress syndrome, cardiac and renal reperfusion injury, thrombosis and glomerulonephritis. In addition to the chemotaxis effect on neutrophils, IL-8 apparently also has the ability to activate neutrophils. Thus, reduction in IL-8 levels could lead to diminished neutrophil infiltration.
Substituted imidazole and fused imidazole compounds have been described for use in the treatment of cytokine mediated diseases by inhibition of proinflammatory cytokines, such as IL-1, IL-6, IL-8 and TNF. Substituted imidazoles for use in the treatment of cytokine mediated diseases have been described in WO 93/14081; WO 96/21452; and WO 96/21654 (each of which is incorporated herein by reference in its entirety). Substituted imidazoles for use in the treatment of inflammation has been described in U.S. Pat. No. 3,929,807 (which is incorporated herein by reference in its entirety). Substituted fused imidazole compounds for use in the treatment of cytokine mediated diseases have been described in WO 88/01169; WO 90/15534; WO 91/00092; WO 92/10190; WO 92/10498; WO 92/12154; and WO 95/35304 (each of which is incorporated herein by reference in its entirety).
Several classes of diamino substituted azaindole compounds have been reported to be useful in the treatment of a variety of diseases including inflammation (U.S. Pat. No. 5,502,187, which is incorporated herein by reference in its entirety). Several classes of substituted indole and azaindole compounds are known to be useful as endothelin receptor antagonists for treating hypertension, renal failure and cerebrovascular disease (WO 94/14434 and WO 95/33748, each of which is incorporated herein by reference in its entirety). A related class of substituted indoles has been reported as useful in the treatment of atherosclerosis (DE 2909779 A1, which is incorporated herein by reference in its entirety). Variously substituted 7-azaindoles have been prepared and reported for use as anti-ulcer drugs (JP 06247966, which is incorporated herein by reference in its entirety).
The preparation of 3-(4-pyridyl)indole compounds has been reported (U.S. Pat. No. 3,551,567; FR 1587692; DE 1795061; Ukr. Kim. Zh. (Russ. Ed.) (1982), 48(1), 76-9; Khim. Geterotsikl. Soedin. (1980), (7), 959-64; each of which is incorporated herein by reference in its entirety). The preparation of 2,3-diphenylindole derivatives has been reported (U.S. Pat. No. 3,654,308; U.S. Pat. No. 3,565,912; and FR 1505197; each of which is incorporated herein by reference in its entirety).
The present invention relates to selected antiinflamatory compounds, analogs and pharmaceutically acceptable salts and prodrugs thereof. The subject compounds are characterized as aryl and heteroaryl substituted fused pyrrole compounds. The invention compounds advantageously treat inflammation related diseases. Therefore, this invention also encompasses pharmaceutical compositions and methods for prophylaxis and treatment of inflamation. The subject invention also relates to processes for making such compounds as well as to intermediates useful in such processes.
In accordance with the present invention, there is provided an anti-inflammatory compound of the Formula: 
or a pharmacutically acceptable salt thereof, wherein
X1 is N, CH or CR1; X2 is N, CH or CR2; X3 is N, CH or CR3; and X4 is N, CH or CR4; provided that at least one of X1, X2, X3 and X4 is N or CH, and that not more than two of X1, X2, X3 and X4 are N; wherein R1, R2, R3 and R4 are each independently xe2x80x94Zxe2x80x94Y;
preferably, X1 is N; X2 is CH or CR2; X3 is CH or CR3; and X4 is CH or CR4; and more preferably, X1 is N; X2 is CR2; X3 is CH or CR3; and X4 is CH;
wherein R2 is independently xe2x80x94Zxe2x80x94Y; and preferably, R2 is independently Y; and R3 is independently xe2x80x94Zxe2x80x94Y; preferably, R3 is halo, trifluoromethyl, phenyl, methyl, hydroxymethyl, hydroxyethyl, dimethylamino, methoxy, trifluoromethoxy, xe2x80x94C(O)xe2x80x94R20, xe2x80x94C(O)xe2x80x94OR21, xe2x80x94C(O)xe2x80x94NR5R21, xe2x80x94S(O)2xe2x80x94R20 or xe2x80x94S(O)2xe2x80x94NR5R21 radicals; more preferably, R3 is halo, trifluoromethyl, phenyl, methyl, hydroxymethyl, hydroxyethyl, dimethylamino, methoxy, trifluoromethoxy, acetyl, methoxycarbonyl, ethoxycarbonyl, amido, N,N-dimethylamido, methylsulfonyl or aminosulfonyl radicals; even more preferably, R3 is halo, trifluoromethyl, phenyl, methyl, hydroxymethyl, hydroxyethyl, methoxy, trifluoromethoxy, acetyl, methoxycarbonyl, ethoxycarbonyl, amido or N,N-dimethylamido radicals; and most preferably, R3 is halo or trifluoromethyl radicals; and R4 is independently xe2x80x94Zxe2x80x94Y; and preferably, R4 is independently Y; or
alternatively, preferably, X1 is N; X2 is CH or CR2; X3 is CH or CR3; and X4 is N; and more preferably, X1 is N; X2 is CR2; X3 is CH or CR3; and X4 is N;
wherein R2 is independently xe2x80x94Zxe2x80x94Y; and preferably, R2 is independently xe2x80x94Zxe2x80x94Y; and R3 is independently xe2x80x94Zxe2x80x94Y; preferably, R3 is halo, trifluoromethyl, phenyl, methyl, hydroxymethyl, hydroxyethyl, dimethylamino, methoxy, trifluoromethoxy, xe2x80x94C(O)xe2x80x94R20, xe2x80x94C(O)xe2x80x94OR21, xe2x80x94C(O)xe2x80x94NR5R21, xe2x80x94S(O)2xe2x80x94R20 or xe2x80x94S(O)2xe2x80x94NR5R21 radicals; and most preferably, R3 is halo, trifluoromethyl, phenyl, methyl, acetyl, hydroxymethyl, hydroxyethyl, dimethylamino, methoxy, trifluoromethoxy, methoxycarbonyl, ethoxycarbonyl, amido, N,N-dimethylamido, methylsulfonyl or aminosulfonyl radicals; or
alternatively, preferably, X1 is N; X2 is CH or CR2; X3 is N; and X4 is CH or CR4; and more preferably, X1 is N; X2 is CR2; X3 is N; and X4 is CH or CR4;
wherein R2 is independently xe2x80x94Zxe2x80x94Y; and preferably, R2 is independently Y; and R4 is independently xe2x80x94Zxe2x80x94Y; preferably, R4 is halo, trifluoromethyl, phenyl, methyl, hydroxyethyl, hydroxymethyl, dimethylamino, methoxy, trifluoromethoxy, xe2x80x94C(O)xe2x80x94R20, xe2x80x94C(O)xe2x80x94OR21, xe2x80x94C(O)xe2x80x94NR5R21, xe2x80x94S(O)2xe2x80x94R20 or xe2x80x94S(O)2xe2x80x94NR5R21 radicals; more preferably, R4 is halo, phenyl, trifluoromethyl, methyl, hydroxymethyl, hydroxyethyl, dimethylamino, methoxy, trifluoromethoxy, acetyl, methoxycarbonyl, ethoxycarbonyl, N,N-dimethylamido, amido, methylsulfonyl or aminosulfonyl radicals; or
alternatively, preferably, X1 is N; X2 is N; X3 is CH or CR3; and X4 is CH or CR4; and more preferably, X1 is N; X2 is N; X3 is CR3; and X4 is CH or CR4;
wherein R3 is independently xe2x80x94Zxe2x80x94Y; and preferably, R3 is independently Y; and R4 is independently xe2x80x94Zxe2x80x94Y; preferably, R4 is halo, trifluoromethyl, phenyl, methyl, hydroxymethyl, hydroxyethyl, dimethylamino, methoxy, trifluoromethoxy, xe2x80x94C(O)xe2x80x94R20, xe2x80x94C(O)xe2x80x94OR21, xe2x80x94C(O)xe2x80x94NR5R21, xe2x80x94S(O)2xe2x80x94R20 or xe2x80x94S(O)2xe2x80x94NR5R21 radicals; and more preferably, R4 is halo, trifluoromethyl, phenyl, methyl, hydroxymethyl, hydroxyethyl, dimethylamino, methoxy, trifluoromethoxy, acetyl, methoxycarbonyl, ethoxycarbonyl, amido, N,N-dimethylamido, methylsulfonyl or aminosulfonyl radicals; or
alternatively, preferably, X1 is CH or CR1; X2 is CH or CR2; X3 is N; and X4 is N; and more preferably, X1 is CH or CR1; X2 is CR2; X3 is N; and X4 is N;
wherein R1 is independently xe2x80x94Zxe2x80x94Y; preferably, R1 is halo, trifluoromethyl, phenyl, methyl, hydroxymethyl, hydroxyethyl, dimethylamino, methoxy, trifluoromethoxy, xe2x80x94C(O)xe2x80x94R20, xe2x80x94C(O)xe2x80x94OR21, xe2x80x94C(O)xe2x80x94NR5R21, xe2x80x94S(O)2xe2x80x94R20 or xe2x80x94S(O)2xe2x80x94NR5R21 radicals; and more preferably, R1 is halo, trifluoromethyl, phenyl, methyl, hydroxymethyl, hydroxyethyl, dimethylamino, methoxy, trifluoromethoxy, acetyl, methoxycarbonyl, ethoxycarbonyl, amido, N,N-dimethylamido, methylsulfonyl or aminosulfonyl radicals; and R2 is independently xe2x80x94Zxe2x80x94Y; and preferably, R2 is independently Y; or
alternatively, preferably, X1 is CH or CR1; X2 is CH or CR2; X3 is CH or CR3; and X4 is CH or CR4, provided that at least one of X1, X2, X3 and X4 is CH; more preferably, X1 is CH; X2 is CH; X3 is CH or CR3; and X4 is CH or CR4; and even more preferably, X1 is CH; X2 is CH; X3 is CR3; and X4 is CH or CR4;
wherein R1 is independently xe2x80x94Zxe2x80x94Y; and preferably, R1 is independently Y; and R2 is independently xe2x80x94Zxe2x80x94Y; and preferably, R2 is independently Y; and R3 is independently xe2x80x94Zxe2x80x94Y; and preferably, R3 is independently Y; and R4 is independently xe2x80x94Zxe2x80x94Y; preferably, R4 is halo, trifluoromethyl, phenyl, methyl, hydroxymethyl, hydroxyethyl, dimethylamino, methoxy, trifluoromethoxy, xe2x80x94C(O)xe2x80x94R20, xe2x80x94C(O)xe2x80x94OR21, xe2x80x94C(O)xe2x80x94NR5R21, xe2x80x94S(O)2xe2x80x94R20 or xe2x80x94S(O)2xe2x80x94NR5R21 radicals; and more preferably, R4 is halo, phenyl, trifluoromethyl, methyl, hydroxymethyl, hydroxyethyl, dimethylamino, methoxy, trifluoromethoxy, acetyl, methoxycarbonyl, ethoxycarbonyl, N,N-dimethylamido, amido, methylsulfonyl or aminosulfonyl radicals; or
alternatively, more preferably, X1 is CH; X2 is CH or CR2; X3 is CH or CR3; and X4 is CH; and even more preferably, X1 is CH; X2 is CR2; X3 is CH or CR3; and X4 is CH;
wherein R2 is independently xe2x80x94Zxe2x80x94Y; and preferably, R2 is independently Y; and R3 is independently xe2x80x94Zxe2x80x94Y; preferably, R3 is halo, trifluoromethyl, phenyl, methyl, hydroxymethyl, hydroxyethyl, dimethylamino, methoxy, trifluoromethoxy, xe2x80x94C(O)xe2x80x94R20, xe2x80x94C(O)xe2x80x94OR21, xe2x80x94C(O)xe2x80x94NR5R21, xe2x80x94S(O)2xe2x80x94R20 or xe2x80x94S(O)2xe2x80x94NR5R21 radicals; and more preferably, R3 is halo, trifluoromethyl, phenyl, methyl, hydroxymethyl, hydroxyethyl, dimethylamino, methoxy, trifluoromethoxy, acetyl, methoxycarbonyl, ethoxycarbonyl, amido, N,N-dimethylamido, methylsulfonyl or aminosulfonyl radicals; and
provided that (1) R2 and R4 are not both substituted or unsubstituted amino radicals; (2) the total number of aryl, heteroaryl, cycloalkyl and heterocyclyl radicals in each xe2x80x94Zxe2x80x94Y is 0-3; and (3) the combined total number of aryl, heteroaryl, cycloalkyl and heterocyclyl radicals in R1, R2, R3 and R4 is 0-4, preferably 0-3;
each Z is independently a (1) bond; (2) alkyl, alkenyl or alkynyl radical optionally substituted by (a) 1-3 radicals of amino, alkylamino, dialkylamino, alkanoylamino, alkoxycarbonylamino, alkylsulfonylamino, hydroxy, alkoxy, alkylthio, cyano or halo, and (b) 1-2 radicals of heterocyclyl, aryl or heteroaryl optionally substituted by 1-3 radicals of amino, alkylamino, dialkylamino, alkanoylamino, alkoxycarbonylamino, alkylsulfonylamino, hydroxy, alkoxy, alkylthio, cyano, halo, alkyl or haloalkyl; (3) heterocyclyl radical optionally substituted by 1-3 radicals of amino, alkylamino, dialkylamino, alkanoylamino, alkoxycarbonylamino, alkylsulfonylamino, hydroxy, alkoxy, alkylthio, cyano, alkyl or haloalkyl; or (4) aryl or heteroaryl radical optionally substituted by 1-3 radicals of amino, alkylamino, dialkylamino, alkanoylamino, alkoxycarbonylamino, alkylsulfonylamino, hydroxy, alkoxy, alkylthio, cyano, halo, alkyl or haloalkyl;
preferably, each Z is independently a (1) bond; (2) C1-C8 alkyl, C2-C8 alkenyl or C2-C8 alkynyl radical optionally substituted by 1-3 radicals of amino, C1-C4 alkylamino, di-(C1-C4 alkyl)amino, C1-C5 alkanoylamino, (C1-C4 alkoxy) carbonylamino, C1-C4 alkylsulfonylamino, hydroxy, C1-C4 alkoxy, C1-C4 alkylthio, cyano, halo, or heterocyclyl, aryl or heteroaryl optionally substituted by 1-3 radicals of amino, C1-C4 alkylamino, di-(C1-C4 alkyl)amino, C1-C5 alkanoylamino, (C1-C4 alkoxy)carbonylamino, C1-C4 alkylsulfonylamino, hydroxy, C1-C4 alkoxy, C1-C4 alkylthio, cyano, halo, C1-C4 alkyl or C1-C4 haloalkyl of 1-3 halo radicals; (3) heterocyclyl radical optionally substituted by 1-3 radicals of amino, C1-C4 alkylamino, di-(C1-C4 alkyl)amino, C1-C5 alkanoylamino, (C1-C4 alkoxy)carbonylamino, C1-C4 alkylsulfonylamino, hydroxy, C1-C4 alkoxy, C1-C4 alkylthio, cyano, C1-C4 alkyl or C1-C4 haloalkyl of 1-3 halo radicals; or (4) aryl or heteroaryl radical optionally substituted by 1-3 radicals of amino, C1-C4 alkylamino, di-(C1-C4 alkyl)amino, C1-C5 alkanoyl amino, (C1-C4 alkoxy)carbonylamino, C1-C4 alkylsulfonyl amino, hydroxy, C1-C4 alkoxy, C1-C4 alkylthio, cyano, halo, C1-C4 alkyl or C1-C4 haloalkyl of 1-3 halo radicals;
more preferably, each Z is independently a (1) bond; (2) C1-C8 alkyl, C2-C8 alkenyl or C2-C8 alkynyl radical optionally substituted by 1-3 radicals of amino, C1-C4 alkylamino, di-(C1-C4 alkyl)amino, C1-C5 alkanoylamino, (C1-C4 alkoxy)carbonylamino, C1-C4 alkylsulfonylamino, hydroxy, C1-C4 alkoxy, C1-C4 alkylthio, halo, or heterocyclyl, aryl or heteroaryl optionally substituted by 1-3 radicals of amino, C1-C4 alkylamino, di-(C1-C4 alkyl)amino, C1-C5 alkanoylamino, (C1-C4 alkoxy)carbonyl amino, C1-C4 alkylsulfonylamino, hydroxy, C1-C4 alkoxy, C1-C4 alkylthio, cyano, halo, C1-C4 alkyl or C1-C4 haloalkyl of 1-3 halo radicals; (3) heterocyclyl radical optionally substituted by 1-2 radicals of amino, C1-C4 alkylamino, di-(C1-C4 alkyl)amino, C1-C5 alkanoylamino, (C1-C4 alkoxy)carbonylamino, C1-C4 alkylsulfonylamino, hydroxy, C1-C4 alkoxy, C1-C4 alkylthio, C1-C4 alkyl or C1-C4 haloalkyl of 1-3 halo radicals; or (4) aryl or heteroaryl radical optionally substituted by 1-3 radicals of amino, C1-C4 alkylamino, di-(C1-C4 alkyl)amino, C1-C5 alkanoylamino, (C1-C4 alkoxy)carbonylamino, C1-C4 alkylsulfonylamino, hydroxy, C1-C4 alkoxy, C1-C4 alkylthio, cyano, halo, C1-C4 alkyl or C1-C4 haloalkyl of 1-3 halo radicals; even more preferably, each Z is independently a (1) bond; (2) C1-C8 alkyl or C2-C8 alkenyl radical optionally substituted by 1-3 radicals of amino, C1-C4 alkylamino, di-(C1-C4 alkyl)amino, C1-C5 alkanoylamino, (C1-C4 alkoxy) carbonylamino, hydroxy, C1-C4 alkoxy, C1-C4 alkylthio, halo, or heterocyclyl, aryl or heteroaryl optionally substituted by 1-3 radicals of amino, C1-C4 alkylamino, di-(C1-C4 alkyl)amino, C1-C5 alkanoylamino, (C1-C4 alkoxy) carbonylamino, hydroxy, C1-C4 alkoxy, C1-C4 alkylthio, cyano, halo, C1-C4 alkyl or C1-C2 haloalkyl of 1-3 halo radicals; (3) heterocyclyl radical optionally substituted by 1-2 radicals of amino, di-(C1-C4 alkyl)amino, (C1-C4 alkoxy)carbonylamino, hydroxy, C1-C4 alkoxy, C1-C4 alkylthio or C1-C4 alkyl radicals; or (4) aryl or heteroaryl radical optionally substituted by 1-3 radicals of amino, C1-C4 alkylamino, di-(C1-C4 alkyl)amino, C1-C5 alkanoylamino, (C1-C4 alkoxy)carbonylamino, C1-C4 alkylsulfonylamino, hydroxy, C1-C4 alkoxy, C1-C4 alkylthio, cyano, halo, C1-C4 alkyl or C1-C2 haloalkyl of 1-3 halo radicals;
yet more preferably, each Z is independently a (1) bond; (2) C1-C4 alkyl or C2-C5 alkenyl radical optionally substituted by 1-3 radicals of amino, di-(C1-C2 alkyl)amino, C1-C5 alkanoylamino, (C1-C4 alkoxy)carbonyl amino, hydroxy, C1-C2 alkoxy, C1-C2 alkylthio, halo, or heterocyclyl, aryl or heteroaryl optionally substituted by 1-3 radicals of amino, C1-C4 alkylamino, di-(C1-C2 alkyl)amino, C1-C5 alkanoylamino, (C1-C4 alkoxy)carbonyl amino, hydroxy, C1-C4 alkoxy, C1-C4 alkylthio, cyano, halo, C1-C4 alkyl or trifluoromethyl radicals; (3) heterocyclyl radical optionally substituted by 1-2 radicals of amino, di-(C1-C2 alkyl)amino, (C1-C4 alkoxy) carbonylamino, hydroxy, C1-C2 alkoxy, C1-C2 alkylthio or C1-C4 alkyl radicals; or (4) aryl or heteroaryl radical optionally substituted by 1-3 radicals of amino, di-(C1-C2 alkyl)amino, C1-C5 alkanoylamino, (C1-C4 alkoxy)carbonyl amino, hydroxy, C1-C2 alkoxy, C1-C2 alkylthio, cyano, halo, C1-C4 alkyl or trifluoromethyl radicals;
yet even more preferably, each Z is independently a (1) bond; (2) C1-C4 alkyl or C2-C5 alkenyl radical optionally substituted by 1-3 radicals of amino, di-(C1-C2 alkyl) amino, (C1-C4 alkoxy)carbonylamino, hydroxy, C1-C2 alkoxy, C1-C2 alkylthio, halo, or aryl or heteroaryl optionally substituted by 1-2 radicals of amino, di-(C1-C2 alkyl) amino, acetamido, (C1-C4 alkoxy)carbonylamino, hydroxy, C1-C2 alkoxy, C1-C2 alkylthio, cyano, halo, C1-C4 alkyl or trifluoromethyl radicals; or (3) aryl or heteroaryl radical optionally substituted by 1-3 radicals of amino, di-(C1-C2 alkyl)amino, acetamido, (C1-C4 alkoxy)carbonyl amino, hydroxy, C1-C2 alkoxy, C1-C2 alkylthio, cyano, halo, C1-C4 alkyl or trifluoromethyl radicals;
still more preferably, each Z is independently a (1) bond; or (2) C1-C4 alkyl radical optionally substituted by 1-2 radicals of amino, di-(C1-C2 alkyl)amino, (C1-C4 alkoxy)carbonylamino, hydroxy, C1-C2 alkoxy, C1-C2 alkyl thio, halo, or aryl or heteroaryl optionally substituted by 1-2 radicals of hydroxy, C1-C2 alkoxy, C1-C2 alkylthio, cyano, halo, C1-C4 alkyl or trifluoromethyl radicals; still even more preferably, each Z is independently a (1) bond; or (2) C1-C4 alkyl radical optionally substituted by 1-2 radicals of amino, t-butoxy carbonylamino, dimethylamino, hydroxy, methoxy, methylthio or halo radicals; and most preferably, each Z is a bond;
each Y is independently a hydrogen radical, provided Z is other than a bond; or halo, cyano, nitro, xe2x80x94C(O)xe2x80x94R20, xe2x80x94C(O)xe2x80x94OR21, xe2x80x94C(O)xe2x80x94NR5R21, xe2x80x94C(NR5)xe2x80x94NR5R21, xe2x80x94OR21, xe2x80x94Oxe2x80x94C(O)xe2x80x94R21, xe2x80x94Oxe2x80x94C(O)xe2x80x94NR5R21, xe2x80x94Oxe2x80x94C(O)xe2x80x94NR22xe2x80x94S(O)2xe2x80x94R20, xe2x80x94SR21, xe2x80x94S(O)xe2x80x94R20, xe2x80x94S(O)2xe2x80x94R20, xe2x80x94S(O)2xe2x80x94NR5R21, xe2x80x94S(O)2xe2x80x94NR22xe2x80x94C(O)xe2x80x94R21, xe2x80x94S(O)2xe2x80x94NR22xe2x80x94C(O)xe2x80x94OR20, xe2x80x94S(O)2xe2x80x94NR22xe2x80x94C(O)xe2x80x94NR5R21, xe2x80x94NR5R21, xe2x80x94NR22xe2x80x94C(O)xe2x80x94R21, xe2x80x94NR22xe2x80x94C(O)xe2x80x94OR20, xe2x80x94NR22xe2x80x94C(O)xe2x80x94NR5R21, xe2x80x94NR22xe2x80x94C(NR5)xe2x80x94NR5R21, xe2x80x94NR22xe2x80x94S(O)2xe2x80x94R20 or xe2x80x94NR22xe2x80x94S(O)2xe2x80x94NR5R21 radical;
preferably, each Y is independently a hydrogen radical, provided Z is other than a bond; or halo, xe2x80x94C(O)xe2x80x94R20, xe2x80x94C(O)xe2x80x94OR21, xe2x80x94C(O)xe2x80x94NR5R21, xe2x80x94C(NR5)xe2x80x94NR5R21, xe2x80x94OR21, xe2x80x94Oxe2x80x94C(O)xe2x80x94R21, xe2x80x94Oxe2x80x94C(O)xe2x80x94NR5R21, xe2x80x94SR21, xe2x80x94S(O)xe2x80x94R20, xe2x80x94S(O)2xe2x80x94R20, xe2x80x94S(O)2xe2x80x94NR5R21, xe2x80x94NR5R21, xe2x80x94NR22xe2x80x94C(O)xe2x80x94R21, xe2x80x94NR22xe2x80x94C(O)xe2x80x94OR20, xe2x80x94NR22xe2x80x94C(O)xe2x80x94NR5R21, xe2x80x94NR22xe2x80x94C(NR5)xe2x80x94NR5R21, xe2x80x94NR22xe2x80x94S(O)2xe2x80x94R20 or xe2x80x94NR22xe2x80x94S(O)2xe2x80x94NR5R21 radical;
more preferably, each Y is independently a hydrogen radical, provided Z is other than a bond; or halo, xe2x80x94C(O)xe2x80x94R20, xe2x80x94C(O)xe2x80x94OR21, xe2x80x94C(O)xe2x80x94NR5R21, xe2x80x94OR21, xe2x80x94SR21, xe2x80x94S(O)xe2x80x94R20, xe2x80x94S(O)2xe2x80x94R20, xe2x80x94S(O)2xe2x80x94NR5R21, xe2x80x94NR5R21, xe2x80x94NR22xe2x80x94C(O)xe2x80x94R21, xe2x80x94NR22xe2x80x94C(O)xe2x80x94OR20, xe2x80x94NR22xe2x80x94C(O)xe2x80x94NR5R21, xe2x80x94NR22xe2x80x94S(O)2xe2x80x94R20 or xe2x80x94NR22xe2x80x94S(O)2xe2x80x94NR5R21 radical;
even more preferably, each Y is independently a hydrogen radical, provided Z is other than a bond; or halo, xe2x80x94C(O)xe2x80x94R20, xe2x80x94C(O)xe2x80x94OR21, xe2x80x94C(O)xe2x80x94NR5R21, xe2x80x94OR21, xe2x80x94SR21, xe2x80x94S(O)xe2x80x94R20, xe2x80x94S(O)2xe2x80x94R20, xe2x80x94S(O)2xe2x80x94NR5R21, xe2x80x94NR5R21, xe2x80x94NR22xe2x80x94C(O)xe2x80x94R21, xe2x80x94NR22xe2x80x94S(O)2xe2x80x94R20 or xe2x80x94NR22xe2x80x94S(O)2xe2x80x94NR5R21 radical;
yet even more preferably, each Y is independently a hydrogen radical, provided Z is other than a bond; or halo, xe2x80x94C(O)xe2x80x94R20, xe2x80x94C(O)xe2x80x94NR5R21, xe2x80x94OR21, xe2x80x94SR21, xe2x80x94S(O)xe2x80x94R20, xe2x80x94NR5R21, xe2x80x94NR22xe2x80x94C(O)xe2x80x94R21, xe2x80x94NR22xe2x80x94S(O)2xe2x80x94R20 or xe2x80x94NR22xe2x80x94S(O)2xe2x80x94NR5R21 radical; and most preferably, each Y is independently a hydrogen radical, provided Z is other than a bond; or halo, xe2x80x94NR5R21, xe2x80x94NR22xe2x80x94C(O)xe2x80x94R21 or xe2x80x94NR22xe2x80x94S(O)2xe2x80x94R20 radical;
wherein each R5 is independently (1) hydrogen radicals; (2) alkyl, alkenyl or alkynyl radicals optionally substituted by 1-3 radicals of amino, alkylamino, dialkylamino, hydroxy, alkoxy, alkylthio, cyano or halo; or (3) aryl, heteroaryl, aralkyl, heteroaralkyl, heterocyclyl, heterocyclylalkyl, cycloalkyl or cycloalkylalkyl radicals optionally substituted by 1-3 radicals of amino, alkylamino, dialkylamino, hydroxy, alkoxy, alkylthio, cyano, alkyl or haloalkyl; and
preferably, each R5 is independently (1) hydrogen radicals; (2) C1-C8 alkyl, C2-C8 alkenyl or C2-C8 alkynyl radicals optionally substituted by 1-3 radicals of amino, C1-C4 alkylamino, di-(C1-C4-alkyl)amino, hydroxy, C1-C4 alkoxy, C1-C4 alkylthio, cyano or halo; or (3) aryl, heteroaryl, aryl-C1-C4-alkyl, heteroaryl-C1-C4-alkyl, heterocyclyl, heterocyclyl-C1-C4-alkyl, C3-C8 cycloalkyl or C3-C8-cycloalkyl-C1-C4-alkyl radicals optionally substituted by 1-3 radicals of amino, C1-C4 alkylamino, di-(C1-C4-alkyl)amino, hydroxy, C1-C4 alkoxy, C1-C4 alkylthio, cyano, C1-C4 alkyl or C1-C4 haloalkyl of 1-3 halo radicals;
more preferably, each R5 is independently (1) hydrogen radicals; (2) C1-C4 alkyl, C2-C5 alkenyl or C2-C5 alkynyl radicals optionally substituted by 1-3 radicals of amino, C1-C4 alkylamino, di-(C1-C4-alkyl)amino, hydroxy, C1-C4 alkoxy, C1-C4 alkylthio or halo; or (3) aryl, heteroaryl, aryl-C1-C4-alkyl, heteroaryl-C1-C4-alkyl, heterocyclyl, heterocyclyl-C1-C4-alkyl, C3-C8 cycloalkyl or C3-C8-cycloalkyl-C1-C4-alkyl radicals optionally substituted by 1-3 radicals of amino, C1-C4 alkylamino, di-(C1-C4-alkyl) amino, hydroxy, C1-C4 alkoxy, C1-C4 alkylthio, cyano, C1-C4 alkyl or C1-C4 haloalkyl of 1-3 halo radicals;
even more preferably, each R5 is independently (1) hydrogen radicals; (2) C1-C4 alkyl or C2-C5 alkenyl radicals optionally substituted by 1-3 radicals of amino, di-(C1-C4-alkyl)amino, hydroxy, C1-C4 alkoxy, C1-C4 alkylthio or halo; or (3) phenyl-C1-C2-alkyl, heteroaryl-C1-C2-alkyl, heterocyclyl-C1-C2-alkyl or C3-C6-cycloalkyl-C1-C2-alkyl radicals optionally substituted by 1-3 radicals of amino, di-(C1-C4-alkyl)amino, hydroxy, C1-C4 alkoxy, C1-C4 alkylthio, cyano, C1-C4 alkyl or C1-C2 haloalkyl of 1-3 halo radicals;
yet even more preferably, each R5 is independently (1) hydrogen radical; (2) C1-C4 alkyl radical optionally substituted by 1-3 radicals of amino, di-(C1-C2-alkyl)amino, hydroxy, C1-C2 alkoxy, C1-C2 alkylthio or halo; or (3) phenyl-C1-C2-alkyl, heteroaryl-C1-C2-alkyl, heterocyclyl-C1-C2-alkyl or C3-C6-cycloalkyl-C1-C2-alkyl radicals optionally substituted by 1-3 radicals of amino, di-(C1-C2-alkyl)amino, hydroxy, C1-C2 alkoxy, C1-C2 alkylthio, methoxy, methylthio, cyano, C1-C4 alkyl or trifluoromethyl radicals;
still more preferably, each R5 is independently (1) hydroqen radical; (2) C1-C4 alkyl radical optionally substituted by 1-3 halo radicals; or (3) phenyl-C1-C2-alkyl or heteroaryl-C1-C2-alkyl, radicals optionally substituted by 1-3 radicals of amino, dimethylamino, hydroxy, methoxy, methylthio, methyl or trifluoromethyl radicals; still even more preferably, each R5 is independently hydrogen or C1-C4 alkyl radical; and most preferably, each R5 is a hydrogen radical;
wherein each R20 is independently (1) alkyl, alkenyl or alkynyl radicals optionally substituted by 1-3 radicals of xe2x80x94CO2R23, amino, alkylamino, dialkylamino, alkanoylamino, alkoxycarbonylamino, N-(alkoxycarbonyl)-N-(alkyl)amino, aminocarbonylamino, alkylsulfonylamino, hydroxy, alkoxy, alkylthio, alkylsulfonyl, alkylsulfonyl, cyano, halo or aralkoxy, aralkylthio, aralkylsulfonyl, cycloalkyl, heterocyclyl, aryl or heteroaryl radicals optionally substituted by 1-3 radicals of amino, alkylamino, dialkylamino, alkanoylamino, alkoxycarbonyl amino, alkylsulfonylamino, alkanoyl, alkoxycarbonyl, hydroxy, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, cyano, halo, alkyl or haloalkyl; (2) heterocyclyl radical optionally substituted by 1-3 radicals of amino, alkylamino, dialkylamino, alkanoylamino, alkoxycarbonylamino, alkylsulfonylamino, alkoxycarbonyl, hydroxy, alkoxy, alkylthio, cyano, alkyl or haloalkyl; or (3) aryl or heteroaryl radicals optionally substituted by 1-3 radicals of amino, alkylamino, dialkylamino, alkanoylamino, alkoxycarbonylamino, alkylsulfonylamino, alkoxycarbonyl, hydroxy, alkoxy, alkylthio, cyano, halo, azido, alkyl or haloalkyl;
preferably, each R20 is independently (1) C1-C8 alkyl, C2-C8 alkenyl or C2-C8 alkynyl radicals optionally substituted by 1-3 radicals of xe2x80x94CO2R23, amino, C1-C4 alkylamino, di-(C1-C4 alkyl)amino, C1-C5 alkanoylamino, (C1-C4 alkoxy)carbonylamino, N-((C1-C4 alkoxy)carbonyl)-N-(C1-C4 alkyl)amino, aminocarbonylamino, C1-C4 alkyl sulfonylamino, hydroxy, C1-C4 alkoxy, C1-C4 alkylthio, C1-C4 alkylsulfinyl, C1-C4 alkylsulfonyl, cyano, halo or aryl-C1-C4-alkoxy, aryl-C1-C4-alkylthio, aryl-C1-C4-alkylsulfonyl, C3-C8 cycloalkyl, heterocyclyl, aryl or heteroaryl radicals optionally substituted by 1-3 radicals of amino, C1-C4 alkylamino, di-(C1-C4 alkyl) amino, C1-C5 alkanoylamino, (C1-C4 alkoxy)carbonylamino, C1-C4 alkylsulfonylamino, C1-C5 alkanoyl, (C1-C4 alkoxy) carbonyl, hydroxy, C1-C4 alkoxy, C1-C4 alkylthio, C1-C4 alkylsulfinyl, C1-C4 alkylsulfonyl, cyano, halo, C1-C4 alkyl or C1-C4 haloalkyl of 1-3 halo radicals; (2) heterocyclyl radical optionally substituted by 1-3 radicals of amino, C1-C4 alkylamino, di-(C1-C4 alkyl)amino, C1-C5 alkanoylamino, (C1-C4 alkoxy)carbonyl amino, C1-C4 alkylsulfonylamino, (C1-C4 alkoxy)carbonyl, hydroxy, C1-C4 alkoxy, C1-C4 alkylthio, cyano, C1-C4 alkyl or C1-C4 haloalkyl of 1-3 halo radicals; or (3) aryl or heteroaryl radicals optionally substituted by 1-3 radicals of amino, C1-C4 alkylamino, di-(C1-C4 alkyl) amino, C1-C5 alkanoylamino, (C1-C4 alkoxy)carbonylamino, C1-C4 alkylsulfonylamino, (C1-C4 alkoxy)carbonyl, hydroxy, C1-C4 alkoxy, C1-C4 alkylthio, cyano, halo, azido, C1-C4 alkyl or C1-C4 haloalkyl of 1-3 halo radicals;
more preferably, each R20 is independently (1) C1-C8 alkyl, C2-C5 alkenyl or C2-C5 alkynyl radicals optionally substituted by 1-3 radicals of xe2x80x94CO2R23, amino, C1-C4 alkyl amino, di-(C1-C4 alkyl)amino, C1-C5 alkanoylamino, (C1-C4 alkoxy)carbonylamino, N-((C1-C4 alkoxy)carbonyl)-N-(C1-C4 alkyl)amino, aminocarbonylamino, C1-C4 alkylsulfonylamino, hydroxy, C1-C4 alkoxy, C1-C4 alkylthio, C1-C4 alkyl sulfinyl, C1-C4 alkylsulfonyl, halo or aryl-C1-C4-alkoxy, aryl-C1-C4-alkylthio, aryl-C1-C4-alkylsulfonyl, C3-C8 cycloalkyl, heterocyclyl, aryl or heteroaryl radicals optionally substituted by 1-3 radicals of amino, C1-C4 alkylamino, di-(C1-C4 alkyl)amino, C1-C5 alkanoylamino, (C1-C4 alkoxy)carbonylamino, C1-C4 alkylsulfonylamino, C1-C5 alkanoyl, (C1-C4 alkoxy)carbonyl, hydroxy, C1-C4 alkoxy, C1-C4 alkylthio, C1-C4 alkylsulfinyl, C1-C4 alkyl sulfonyl, cyano, halo, C1-C4 alkyl or C1-C4 haloalkyl of 1-3 halo radicals; (2) heterocyclyl radical optionally substituted by 1-3 radicals of amino, C1-C4 alkylamino, di-(C1-C4 alkyl)amino, C1-C5 alkanoylamino, (C1-C4 alkoxy)carbonylamino, C1-C4 alkylsulfonylamino, (C1-C4 alkoxy)carbonyl, hydroxy, C1-C4 alkoxy, C1-C4 alkylthio, C1-C4 alkyl or C1-C4 haloalkyl of 1-3 halo radicals; or (3) aryl or heteroaryl radicals optionally substituted by 1-3 radicals of amino, C1-C4 alkylamino, di-(C1-C4 alkyl) amino, C1-C5 alkanoylamino, (C1-C4 alkoxy)carbonylamino, C1-C4 alkylsulfonylamino, (C1-C4 alkoxy)carbonyl, hydroxy, C1-C4 alkoxy, C1-C4 alkylthio, cyano, halo, azido, C1-C4 alkyl or C1-C4 haloalkyl of 1-3 halo radicals;
even more preferably, each R20 is independently (1) C1-C8 alkyl or C2-C5 alkenyl radicals optionally substituted by 1-3 radicals of xe2x80x94CO2R23, amino, C1-C4 alkylamino, di-(C1-C4 alkyl)amino, C1-C5 alkanoylamino, (C1-C4 alkoxy) carbonylamino, N-((C1-C4 alkoxy)carbonyl)-N-(C1-C4 alkyl)amino, aminocarbonylamino, hydroxy, C1-C4 alkoxy, C1-C4 alkylthio, C1-C4 alkylsulfinyl, C1-C4 alkylsulfonyl, halo or aryl-C1-C4-alkoxy, aryl-C1-C4-alkylthio, aryl-C1-C4-alkylsulfonyl, C3-C6 cycloalkyl, heterocyclyl, aryl or heteroaryl radicals optionally substituted by 1-3 radicals of amino, C1-C4 alkylamino, di-(C1-C4 alkyl) amino, C1-C5 alkanoylamino, (C1-C4 alkoxy)carbonylamino, C1-C4 alkylsulfonylamino, C1-C5 alkanoyl, (C1-C4 alkoxy) carbonyl, hydroxy, C1-C4 alkoxy, C1-C4 alkylthio, cyano, halo, C1-C4 alkyl or C1-C2 haloalkyl of 1-3 halo radicals; (2) heterocyclyl radical optionally substituted by 1-2 radicals of amino, C1-C4 alkylamino, di-(C1-C4 alkyl) amino, C1-C5 alkanoylamino, (C1-C4 alkoxy)carbonylamino, (C1-C4 alkoxy)carbonyl, hydroxy, C1-C4 alkoxy, C1-C4 alkylthio or C1-C4 alkyl; or (3) aryl or heteroaryl radicals optionally substituted by 1-3 radicals of amino, C1-C4 alkylamino, di-(C1-C4 alkyl)amino, C1-C5 alkanoyl amino, (C1-C4 alkoxy)carbonylamino, C1-C4 alkylsulfonyl amino, (C1-C4 alkoxy)carbonyl, hydroxy, C1-C4 alkoxy, C1-C4 alkylthio, cyano, halo, azido, C1-C4 alkyl or C1-C2 haloalkyl of 1-3 halo radicals;
yet more preferably, each R20 is independently (1) C1-C8 alkyl or C2-C5 alkenyl radicals optionally substituted by 1-3 radicals of xe2x80x94CO2R23, amino, C1-C4 alkylamino, di-(C1-C4 alkyl)amino, C1-C5 alkanoylamino, (C1-C4 alkoxy) carbonylamino, N-((C1-C4 alkoxy)carbonyl)-N-(C1-C4 alkyl) amino, aminocarbonylamino, hydroxy, C1-C4 alkoxy, C1-C4 alkylthio, C1-C4 alkylsulfinyl, C1-C4 alkylsulfonyl, halo or aryl-C1-C4-alkoxy, aryl-C1-C4-alkylthio, aryl-C1-C4-alkylsulfonyl, C3-C6 cycloalkyl, heterocyclyl, aryl or heteroaryl radicals optionally substituted by 1-3 radicals of amino, C1-C4 alkylamino, di-(C1-C4 alkyl) amino, C1-C5 alkanoylamino, (C1-C4 alkoxy)carbonylamino, C1-C4 alkylsulfonylamino, C1-C5 alkanoyl, (C1-C4 alkoxy) carbonyl, hydroxy, C1-C4 alkoxy, C1-C4 alkylthio, cyano, halo, C1-C4 alkyl or C1-C2 haloalkyl of 1-3 halo radicals; (2) heterocyclyl radical optionally substituted by 1-2 radicals of amino, di-(C1-C4 alkyl)amino, (C1-C4 alkoxy) carbonylamino, (C1-C4 alkoxy)carbonyl, hydroxy, C1-C4 alkoxy, C1-C4 alkylthio or C1-C4 alkyl; or (3) aryl or heteroaryl radicals optionally substituted by 1-2 radicals of amino, di-(C1-C4 alkyl)amino, acetamido, (C1-C4 alkoxy)carbonylamino, C1-C4 alkylsulfonylamino, (C1-C4 alkoxy)carbonyl, hydroxy, C1-C4 alkoxy, C1-C4 alkylthio, cyano, halo, azido, C1-C4 alkyl or trifluoromethyl radicals;
still more preferably, each R20 is independently (1) C1-C8 alkyl radicals optionally substituted by 1-3 radicals of xe2x80x94CO2R23, amino, C1-C4 alkylamino, di-(C1-C4 alkyl)amino, C1-C5 alkanoylamino, (C1-C4 alkoxy)carbonylamino, N-((C1-C4 alkoxy)carbonyl)-N-(C1-C4 alkyl)amino, aminocarbonyl amino, hydroxy, C1-C4 alkoxy, C1-C4 alkylthio, C1-C4 alkylsulfinyl, C1-C4 alkylsulfonyl, halo or C3-C6 cycloalkyl, heterocyclyl, aryl or heteroaryl radicals optionally substituted by 1-2 radicals of amino, di-(C1-C4 alkyl)amino, C1-C5 alkanoylamino, (C1-C4 alkoxy)carbonyl amino, C1-C4 alkylsulfonylamino, (C1-C4 alkoxy)carbonyl, hydroxy, C1-C4 alkoxy, C1-C4 alkylthio, cyano, halo, C1-C4 alkyl or trifluoromethyl radicals; (2) heterocyclyl radical optionally substituted by 1-2 radicals of (C1-C4 alkoxy)carbonyl, hydroxy, C1-C4 alkoxy, C1-C4 alkylthio or C1-C4 alkyl; or (3) aryl or heteroaryl radicals optionally substituted by 1-2 radicals of (C1-C4 alkoxy)carbonyl, hydroxy, C1-C4 alkoxy, C1-C4 alkylthio, cyano, halo, azido, C1-C4 alkyl or trifluoromethyl radicals;
still even more preferably, each R20 is independently (1) C1-C6 alkyl radicals optionally substituted by 1-3 radicals of xe2x80x94CO2R23, amino, methylamino, dimethylamino, t-butoxycarbonylamino, N-((t-butoxy)carbonyl)-N-(methyl) amino, aminocarbonylamino, hydroxy, butoxy, methoxy, butylthio, methylthio, methylsulfinyl, methylsulfonyl, halo or C5-C6 cycloalkyl, heterocyclyl, phenyl or heteroaryl radicals optionally substituted by 1-2 radicals of amino, dimethylamino, acetamino, hydroxy, methoxy, methylthio, halo, methyl or trifluoromethyl radicals; (2) heterocyclyl radical optionally substituted by 1-2 radicals of t-butoxycarbonyl, hydroxy, or C1-C4 alkyl; or (3) aryl or heteroaryl radicals optionally substituted by 1-2 radicals of t-butoxycarbonyl, hydroxy, methoxy, methylthio, cyano, halo, azido, methyl or trifluoromethyl radicals; and
most preferably, each R20 is-independently (1) C1-C6 alkyl radicals optionally substituted by 1-3 radicals of xe2x80x94CO2R23, amino, methylamino, dimethylamino, t-butoxy carbonylamino, N-((t-butoxy)carbonyl)-N-(methyl)amino, aminocarbonylamino, hydroxy, butoxy, methoxy, butylthio, methylthio, methylsulfinyl, methylsulfonyl, halo or C5-C6 cycloalkyl, heterocyclyl, phenyl or heteroaryl radicals optionally substituted by 1-2 radicals of amino, dimethylamino, acetamino, hydroxy, methoxy, methylthio, halo, methyl or trifluoromethyl radicals; (2) heterocyclyl radical optionally substituted by t-butoxycarbonyl; or (3) aryl or heteroaryl radicals optionally substituted by 1-2 radicals of t-butoxy carbonyl, hydroxy, methoxy, halo, azido, methyl or trifluoromethyl radicals;
each R21 is independently hydrogen radical or R20;
each R22 is independently (1) hydrogen radical; (2) alkyl radical optionally substituted by a radical of heterocyclyl, aryl or heteroaryl optionally substituted by 1-3 radicals of amino, alkylamino, dialkylamino, alkanoylamino, alkoxycarbonylamino, alkylsulfonylamino, hydroxy, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, cyano, halo, alkyl or haloalkyl; or (3) heterocyclyl, aryl or heteroaryl radicals optionally substituted by 1-3 radicals of amino, alkylamino, dialkylamino, alkanoylamino, alkoxycarbonylamino, alkylsulfonylamino, hydroxy, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, cyano, halo, alkyl or haloalkyl; and
preferably, each R22 is independently (1) hydrogen radical; (2) C1-C4 alkyl radical optionally substituted by a radical of heterocyclyl, aryl or heteroaryl optionally substituted by 1-3 radicals of amino, C1-C4 alkylamino, di-(C1-C4 alkyl)amino, C1-C5 alkanoylamino, (C1-C4 alkoxy) carbonylamino, C1-C4 alkylsulfonylamino, hydroxy, C1-C4 alkoxy, C1-C4 alkylthio, C1-C4 alkylsulfinyl, C1-C4 alkyl sulfonyl, cyano, halo, C1-C4 alkyl or C1-C4 haloalkyl of 1-3 halo radicals; or (3) heterocyclyl, aryl or heteroaryl radicals optionally substituted by 1-3 radicals of amino, C1-C4 alkylamino, di-(C1-C4 alkyl) amino, C1-C5 alkanoylamino, (C1-C4 alkoxy)carbonylamino, C1-C4 alkylsulfonylamino, hydroxy, C1-C4 alkoxy, C1-C4 alkylthio, C1-C4 alkylsulfinyl, C1-C4 alkylsulfonyl, cyano, halo, C1-C4 alkyl or C1-C4 haloalkyl of 1-3 halo radicals;
more preferably, each R22 is independently (1) hydrogen radical; or (2) C1-C4 alkyl radical optionally substituted by a radical of phenyl or heteroaryl optionally substituted by 1-3 radicals of amino, di-(C1-C2 alkyl) amino, C1-C5 alkanoylamino, (C1-C4 alkoxy)carbonylamino, hydroxy, C1-C4 alkoxy, C1-C4 alkylthio, cyano, halo, C1-C4 alkyl or C1-C2 haloalkyl of 1-3 halo radicals; even more preferably, each R22 is independently hydrogen or C1-C4 alkyl radical; and most preferably, each R22 is independently hydrogen or methyl radical;
each R23 is independently hydrogen or alkyl, or aryl, heteroaryl, aralkyl or heteroaralkyl optionally substituted by 1-3 radicals of amino, alkylamino, dialkylamino, alkanoylamino, alkoxycarbonylamino, alkylsulfonylamino, hydroxy, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, cyano, halo, alkyl or haloalkyl; and
preferably, each R23 is independently hydrogen or C1-C4 alkyl, or aryl, heteroaryl, aryl-C1-C4-alkyl or heteroaryl-C1-C4-alkyl optionally substituted by 1-3 radicals of amino, C1-C4 alkylamino, di-(C1-C4 alkyl) amino, C1-C5 alkanoylamino, (C1-C4 alkoxy)carbonylamino, C1-C4 alkylsulfonylamino, hydroxy, C1-C4 alkoxy, C1-C4 alkylthio, C1-C4 alkylsulfinyl, C1-C4 alkylsulfonyl, cyano, halo, C1-C4 alkyl or C1-C4 haloalkyl of 1-3 halo radicals;
more preferably, each R23 is independently hydrogen or C1-C4 alkyl, or phenyl, heteroaryl, phenyl-C1-C2-alkyl or heteroaryl-C1-C2-alkyl optionally substituted by 1-3 radicals of amino, di-(C1-C4 alkyl)amino, C1-C5 alkanoylamino, (C1-C4 alkoxy)carbonylamino, hydroxy, C1-C4 alkoxy, C1-C4 alkylthio, cyano, halo, C1-C4 alkyl or C1-C2 haloalkyl of 1-3 halo radicals;
even more preferably, each R23 is independently hydrogen or C1-C4 alkyl, or phenyl, heteroaryl, phenyl-C1-C2-alkyl or heteroaryl-C1-C2-alkyl optionally substituted by 1-3 radicals of amino, di-(C1-C2 alkyl)amino, C1-C5 alkanoylamino, (C1-C4 alkoxy)carbonylamino, hydroxy, C1-C2 alkoxy, C1-C2 alkylthio, cyano, halo, C1-C4 alkyl or trifluoromethyl radicals;
yet more preferably, each R23 is independently hydrogen or C1-C4 alkyl, or phenyl-C1-C2-alkyl or heteroaryl-C1-C2-alkyl optionally substituted by 1-3 radicals of amino, di-(C1-C2 alkyl)amino, acetamido, (C1-C4 alkoxy)carbonyl amino, hydroxy, C1-C2 alkoxy, C1-C2 alkylthio, cyano, halo, C1-C4 alkyl or trifluoromethyl radicals; still more preferably, each R23 is independently hydrogen or C1-C4 alkyl, or phenyl-C1-C2-alkyl optionally substituted by 1-2 radicals of hydroxy, C1-C2 alkoxy, C1-C2 alkylthio, cyano, halo, C1-C4 alkyl or trifluoromethyl radicals; and most preferably, each R23 is independently hydrogen or C1-C4 alkyl radicals;
R10 is a hydrogen, R30, xe2x80x94C(O)xe2x80x94R29, xe2x80x94C(O)xe2x80x94OR30, xe2x80x94C(O)xe2x80x94NR31R32, xe2x80x94S(O)2xe2x80x94R30 or xe2x80x94S(O)2xe2x80x94NR31R32 radical; preferably, R10 is a hydrogen, R30, xe2x80x94C(O)xe2x80x94R29, xe2x80x94C(O)xe2x80x94NR31R32, xe2x80x94S(O)2xe2x80x94R30 or xe2x80x94S(O)2xe2x80x94NR31R32 radical; more preferably, R10 is a hydrogen, R30, xe2x80x94C(O)xe2x80x94R29 or xe2x80x94C(O)xe2x80x94NR31R32 radical; and most preferably, R10 is a hydrogen or methyl radical;
R11 and R12 are each independently an aryl or heteroaryl radical optionally substituted by 1-3 radicals of R30, halo, cyano, xe2x80x94C(O)xe2x80x94R30, xe2x80x94C(O)xe2x80x94OR29, xe2x80x94C(O)xe2x80x94NR31R32, xe2x80x94C(NR31)xe2x80x94NR31R32, xe2x80x94OR29, xe2x80x94Oxe2x80x94C(O)xe2x80x94R29, xe2x80x94Oxe2x80x94C(O)xe2x80x94NR31R32, xe2x80x94Oxe2x80x94C(O)xe2x80x94NR33xe2x80x94S(O)2xe2x80x94R30, xe2x80x94SR29, xe2x80x94S(O)xe2x80x94R30, xe2x80x94S(O)2xe2x80x94R30, xe2x80x94S(O)2xe2x80x94NR31R32, xe2x80x94S(O)2xe2x80x94NR33xe2x80x94C(O)xe2x80x94R30, xe2x80x94S(O)2xe2x80x94NR33xe2x80x94C(O)xe2x80x94OR30, xe2x80x94S(O)2xe2x80x94NR33xe2x80x94C(O)xe2x80x94NR31R32, xe2x80x94NR31R32, xe2x80x94NR33xe2x80x94C(O)xe2x80x94R29, xe2x80x94NR33xe2x80x94C(O)xe2x80x94OR30, xe2x80x94NR33xe2x80x94C(O)xe2x80x94NR31R32, xe2x80x94NR33xe2x80x94C(NR31)xe2x80x94NR31R32, xe2x80x94NR33xe2x80x94S(O)2xe2x80x94R30 or xe2x80x94NR33xe2x80x94S(O)2xe2x80x94NR31R32 radicals;
preferably, R11 and R12 are each independently an aryl or heteroaryl radical optionally substituted by 1-2 radicals of R30, halo, cyano radicals, xe2x80x94C(O)xe2x80x94R30, xe2x80x94C(O)xe2x80x94OR29, xe2x80x94C(O)xe2x80x94NR31R32, xe2x80x94C(NR31)xe2x80x94NR31R32, xe2x80x94OR29, xe2x80x94SR29, xe2x80x94S(O)xe2x80x94R30, xe2x80x94S(O)2xe2x80x94R30, xe2x80x94S(O)2xe2x80x94NR31R32, xe2x80x94NR31R32, xe2x80x94NR33xe2x80x94C(O)xe2x80x94R29 or xe2x80x94NR33xe2x80x94C(O)xe2x80x94OR30 radicals;
more preferably, R11 and R12 are each independently an aryl or heteroaryl radical optionally substituted by 1-2 radicals of R30, halo, cyano, xe2x80x94C(O)xe2x80x94R30, xe2x80x94C(O)xe2x80x94OR29, xe2x80x94C(O)xe2x80x94NR31R32, xe2x80x94C(NR31)xe2x80x94NR31R32, xe2x80x94OR29, xe2x80x94SR29, xe2x80x94S(O)xe2x80x94R30, xe2x80x94S(O)2xe2x80x94R30, xe2x80x94S(O)2xe2x80x94NR31R32, xe2x80x94NR31R32 or xe2x80x94NR33xe2x80x94C(O)xe2x80x94R29 radicals;
even more preferably, R11 and R12 are each independently an aryl or heteroaryl radical optionally substituted by 1-2 radicals of R30, halo, cyano, xe2x80x94C(O)xe2x80x94NR31R32, xe2x80x94OR29, xe2x80x94SR29, xe2x80x94S(O)xe2x80x94R30, xe2x80x94S(O)2xe2x80x94R30, xe2x80x94S(O)2xe2x80x94NR31R32, xe2x80x94NR31R32 or xe2x80x94NR33xe2x80x94C(O)xe2x80x94R29 radicals;
yet more preferably, R11 is a heteroaryl radical optionally substituted by 1-2 radicals of R30, halo, cyano, xe2x80x94C(O)xe2x80x94NR31R32, xe2x80x94OR29, xe2x80x94SR29, xe2x80x94NR31R32 or xe2x80x94NR33xe2x80x94C(O)xe2x80x94R29 radicals; and R12 is an aryl radical optionally substituted by 1-2 radicals of R30, halo, cyano, xe2x80x94C(O)xe2x80x94NR31R32, xe2x80x94OR29, xe2x80x94SR29, xe2x80x94S(O)xe2x80x94R30, S(O)2xe2x80x94R30, xe2x80x94S(O)2xe2x80x94NR31R32, xe2x80x94NR31R32 or xe2x80x94NR33xe2x80x94C(O)xe2x80x94R29 radicals;
still more preferably, R11 is a heteroaryl radical optionally substituted by 1-2 radicals of amino, dimethylamino, acetamido, hydroxy, halo, cyano, methoxy, methyl or trifluoromethyl radicals; and R12 is an aryl radical optionally substituted by 1-2 radicals of amino, dimethylamino, acetamido, hydroxy, halo, cyano, methoxy, methylthio, methylsulfinyl, methylsulfonyl, aminocarbonyl, methyl or trifluoromethyl radicals;
still even more preferably, R11 is a 4-pyridyl, 4-quinolinyl, 4-imidazolyl or 4-pyrimidinyl radical optionally substituted by a radical of amino, dimethylamino, acetamido, hydroxy, halo, cyano, methoxy, methyl or trifluoromethyl radicals; and R12 is an unsubstituted phenyl or naphthyl radical or a phenyl radical substituted by 1-2 radicals of amino, dimethylamino, acetamido, hydroxy, halo, cyano, methoxy, methylthio, methylsulfinyl, methylsulfonyl, aminocarbonyl, methyl or trifluoromethyl radicals; and
most preferably, R11 is a 4-pyridyl radical optionally substituted by a radical of amino, dimethylamino, acetamido, hydroxy, halo, cyano, methoxy, methyl or trifluoromethyl radicals; and R12 is an unsubstituted phenyl radical or a phenyl radical substituted by 1-2 radicals of amino, dimethylamino, acetamido, hydroxy, halo, cyano, methoxy, methylthio, methylsulfonyl, methyl or trifluoromethyl radicals; and
provided that the total number of aryl, heteroaryl, cycloalkyl and heterocyclyl radicals substituted on each of R11 and R12 is 0-1; and provided that when each of X1, X2, X3 and X4 represent carbon atoms, then R11 is a substituted aryl radical and R12 is heteroaryl radical, or R11 is a heteroaryl radical and R12 is a substituted aryl radical;
wherein each R30 is independently (1) alkyl, alkenyl or alkynyl radicals optionally substituted by 1-3 radicals of xe2x80x94NR31R31, xe2x80x94CO2R23, hydroxy, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, cyano, halo or aralkoxy, aralkylthio, aralkylsulfonyl, heterocyclyl, aryl or heteroaryl radicals optionally substituted by 1-3 radicals of amino, alkylamino, dialkylamino, alkanoyl amino, alkoxycarbonylamino, alkylsulfonylamino, hydroxy, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, cyano, halo, alkyl or haloalkyl; (2) heterocyclyl radical optionally substituted by 1-3 radicals of amino, alkylamino, dialkylamino, alkanoylamino, alkoxycarbonyl amino, alkylsulfonylamino, hydroxy, alkoxy, alkylthio, cyano, alkyl or haloalkyl; or (3) aryl or heteroaryl radicals optionally substituted by 1-3 radicals of amino, alkylamino, dialkylamino, alkanoylamino, alkoxycarbonyl amino, alkylsulfonylamino, hydroxy, alkoxy, alkylthio, cyano, halo, alkyl or haloalkyl;
preferably, each R30 is independently (1) C1-C4 alkyl, C2-C4 alkenyl or C2-C4 alkynyl radicals optionally substituted by 1-3 radicals of xe2x80x94NR31R31, xe2x80x94CO2R23, hydroxy, C1-C4 alkoxy, C1-C4 alkylthio, C1-C4 alkylsulfinyl, C1-C4 alkylsulfonyl, cyano, halo or aryl-C1-C4-alkoxy, aryl-C1-C4-alkylthio, aryl-C1-C4-alkylsulfonyl, heterocyclyl, aryl or heteroaryl radicals optionally substituted by 1-3 radicals of amino, C1-C4 alkylamino, di-(C1-C4 alkyl) amino, C1-C5 alkanoylamino, (C1-C4 alkoxy)carbonylamino, C1-C4 alkylsulfonylamino, hydroxy, C1-C4 alkoxy, C1-C4 alkylthio, C1-C4 alkylsulfinyl, C1-C4 alkylsulfonyl, cyano, halo, C1-C4 alkyl or C1-C4 haloalkyl of 1-3 halo radicals; (2) heterocyclyl radical optionally substituted by 1-3 radicals of amino, C1-C4 alkylamino, di-(C1-C4 alkyl)amino, C1-C5 alkanoylamino, (C1-C4 alkoxy)carbonyl amino, C1-C4 alkylsulfonylamino, hydroxy, C1-C4 alkoxy, C1-C4 alkylthio, cyano, C1-C4 alkyl or C1-C4 haloalkyl of 1-3 halo radicals; or (3) aryl or heteroaryl radicals optionally substituted by 1-3 radicals of amino, C1-C4 alkylamino, di-(C1-C4 alkyl)amino, C1-C5 alkanoylamino, (C1-C4 alkoxy)carbonylamino, C1-C4 alkylsulfonylamino, hydroxy, C1-C4 alkoxy, C1-C4 alkylthio, cyano, halo, C1-C4 alkyl or C1-C4 haloalkyl of 1-3 halo radicals;
more preferably, each R30 is independently (1) C1-C4 alkyl radical optionally substituted by 1-3 radicals of (a) xe2x80x94NR31R31; (b) C1-C4 alkoxy-carbonyl or phenoxycarbonyl or phenylmethoxycarbonyl optionally substituted by 1-3 radicals of amino, alkylamino, di-(C1-C4-alkyl)amino, C1-C5 alkanoylamino, (C1-C4 alkoxy)carbonylamino, C1-C4 alkyl sulfonylamino, hydroxy, C1-C4 alkoxy, C1-C4 alkylthio, cyano, halo, C1-C4 alkyl or trifluoromethyl; or (c) hydroxy, C1-C4 alkoxy, C1-C4 alkylthio, or phenyl-C1-C4-alkoxy, phenyl-C1-C4-alkylthio, heterocyclyl, phenyl or heteroaryl radicals optionally substituted by 1-3 radicals of amino, C1-C4 alkylamino, di-(C1-C4 alkyl) amino, C1-C5 alkanoylamino, (C1-C4 alkoxy)carbonylamino, hydroxy, C1-C4 alkoxy, C1-C4 alkylthio, cyano, halo, C1-C4 alkyl or C1-C4 haloalkyl of 1-3 halo radicals; (2) C1-C4 haloalkyl of 1-3 halo radical; or (3) aryl or heteroaryl radicals optionally substituted by 1-3 radicals of amino, C1-C4 alkylamino, di-(C1-C4 alkyl)amino, C1-C5 alkanoylamino, (C1-C4 alkoxy)carbonylamino, hydroxy, C1-C4 alkoxy, C1-C4 alkylthio, cyano, halo, C1-C4 alkyl or trifluoromethyl radicals;
even more preferably, each R30 is independently (1) C1-C4 alkyl radical optionally substituted by (a) amino, C1-C4 alkylamino or di-(C1-C4-alkyl)amino radicals; or (b) hydroxy, C1-C4 alkoxy, heterocyclyl, phenyl or heteroaryl radicals optionally substituted by 1-3 radicals of amino, C1-C4 alkylamino, di-(C1-C4 alkyl)amino, C1-C5 alkanoylamino, (C1-C4 alkoxy)carbonylamino, hydroxy, C1-C4 alkoxy, C1-C4 alkylthio, cyano, halo, C1-C4 alkyl or trifluoromethyl radicals; (2) C1-C2 haloalkyl of 1-3 halo radical; or (3) aryl or heteroaryl radicals optionally substituted by 1-3 radicals of amino, C1-C4 alkylamino, di-(C1-C4 alkyl)amino, C1-C5 alkanoylamino, (C1-C4 alkoxy) carbonylamino, hydroxy, C1-C4 alkoxy, C1-C4 alkylthio, cyano, halo, C1-C4 alkyl or trifluoromethyl radicals;
yet more preferably, each R30 is independently (1) C1-C4 alkyl radical optionally substituted by a phenyl or heteroaryl radical optionally substituted by 1-3 radicals of amino, di-(C1-C2 alkyl)amino, acetamido, hydroxy, C1-C2 alkoxy, halo, C1-C4 alkyl or trifluoromethyl radicals; (2) trifluoromethyl radical; or (3) aryl or heteroaryl radicals optionally substituted by 1-3 radicals of amino, di-(C1-C2 alkyl)amino, acetamido, hydroxy, C1-C2 alkoxy, halo, C1-C4 alkyl or trifluoromethyl radicals;
still more preferably, each R30 is independently (1) C1-C4 alkyl radical optionally substituted by a phenyl or heteroaryl radical optionally substituted by 1-3 radicals of amino, dimethylamino, acetamido, hydroxy, halo, methoxy, methyl or trifluoromethyl radicals; (2) trifluoromethyl radical; or (3) aryl or heteroaryl radicals optionally substituted by 1-3 radicals of amino, dimethylamino, acetamido, hydroxy, halo, methoxy, methyl or trifluoromethyl radicals; and most preferably, R30 is independently (1) C1-C4 alkyl radical optionally substituted by a phenyl or heteroaryl radical optionally substituted by 1-2 radicals of amino, dimethylamino, acetamido, hydroxy, halo, methoxy, methyl or trifluoromethyl radicals; (2) trifluoromethyl radical; or (3) aryl or heteroaryl radicals optionally substituted by 1-3 radicals of amino, dimethylamino, acetamido, hydroxy, halo, methoxy, methyl or trifluoromethyl radicals;
each R29 is independently hydrogen radical or R30; and preferably, R29 is an aryl or heteroaryl radicals optionally substituted by 1-2 radicals of amino, dimethylamino, acetamido, hydroxy, halo, methoxy, methyl or trifluoromethyl radicals;
each R31 is independently (1) hydrogen radicals; (2) alkyl radical optionally substituted by an cycloalkyl, aryl, heterocyclyl or heteroaryl radical optionally substituted by 1-3 radicals of amino, alkylamino, dialkylamino, alkanoylamino, alkoxycarbonylamino, alkylsulfonylamino, hydroxy, alkoxy, alkylthio, cyano, alkyl or haloalkyl; or (3) aryl, heteroaryl, heterocyclyl or cycloalkyl radical optionally substituted by 1-3 radicals of amino, alkylamino, dialkylamino, alkanoylamino, alkoxycarbonylamino, alkylsulfonylamino, hydroxy, alkoxy, alkylthio, cyano, alkyl or haloalkyl;
preferably, each R31 is independently (1) hydrogen radicals; (2) C1-C4 alkyl radical optionally substituted by an C3-C8 cycloalkyl, aryl, heterocyclyl or heteroaryl radical optionally substituted by 1-3 radicals of amino, C1-C4 alkylamino, di-(C1-C4 alkyl)amino, C1-C5 alkanoyl amino, (C1-C4 alkoxy)carbonylamino, C1-C4 alkylsulfonyl amino, hydroxy, C1-C4 alkoxy, C1-C4 alkylthio, cyano, C1-C4 alkyl or C1-C4 haloalkyl of 1-3 halo radicals; or (3) aryl, heteroaryl, heterocyclyl or C3-C8 cycloalkyl radical optionally substituted by 1-3 radicals of amino, C1-C4 alkylamino, di-(C1-C4 alkyl)amino, C1-C5 alkanoylamino, (C1-C4 alkoxy)carbonylamino, C1-C4 alkylsulfonylamino, hydroxy, C1-C4 alkoxy, C1-C4 alkylthio, cyano, C1-C4 alkyl or C1-C4 haloalkyl of 1-3 halo radicals;
more preferably, each R31 is independently (1) hydrogen radicals; or (2) C1-C4 alkyl radical optionally substituted by an phenyl or heteroaryl radical optionally substituted by 1-3 radicals of amino, C1-C4 alkylamino, di-(C1-C4 alkyl)amino, C1-C5 alkanoylamino, (C1-C4 alkoxy)carbonylamino, hydroxy, C1-C4 alkoxy, C1-C4 alkylthio, cyano, C1-C4 alkyl or trifluoromethyl radicals; even more preferably, each R31 is independently hydrogen or C1-C4 alkyl radicals; and most preferably, R31 is independently hydrogen, methyl or ethyl radicals;
each R32 is independently (1) hydrogen radicals; (2) alkyl radical optionally substituted by an cycloalkyl, aryl, heterocyclyl or heteroaryl radical optionally substituted by 1-3 radicals of amino, alkylamino, dialkylamino, alkanoylamino, alkoxycarbonylamino, alkylsulfonylamino, hydroxy, alkoxy, alkylthio, cyano, alkyl or haloalkyl; or (3) aryl, heteroaryl, heterocyclyl or cycloalkyl radical optionally substituted by 1-3 radicals of amino, alkylamino, dialkylamino, alkanoylamino, alkoxycarbonylamino, alkylsulfonylamino, hydroxy, alkoxy, alkylthio, cyano, alkyl or haloalkyl;
preferably, each R32 is independently (1) hydrogen radicals; (2) C1-C4 alkyl radical optionally substituted by an C3-C8 cycloalkyl, aryl, heterocyclyl or heteroaryl radical optionally substituted by 1-3 radicals of amino, C1-C4 alkylamino, di-(C1-C4 alkyl)amino, C1-C5 alkanoyl amino, (C1-C4 alkoxy)carbonylamino, C1-C4 alkylsulfonyl amino, hydroxy, C1-C4 alkoxy, C1-C4 alkylthio, cyano, C1-C4 alkyl or C1-C4 haloalkyl of 1-3 halo radicals; or (3) aryl, heteroaryl, heterocyclyl or C3-C8 cycloalkyl radical optionally substituted by 1-3 radicals of amino, C1-C4 alkylamino, di-(C1-C4 alkyl)amino, C1-C5 alkanoylamino, (C1-C4 alkoxy)carbonylamino, C1-C4 alkylsulfonylamino, hydroxy, C1-C4 alkoxy, C1-C4 alkylthio, cyano, C1-C4 alkyl or C1-C4 haloalkyl of 1-3 halo radicals;
more preferably, each R32 is independently (1) hydrogen radicals; (2) C1-C4 alkyl radical optionally substituted by an C3-C6 cycloalkyl, aryl, heterocyclyl or heteroaryl radical optionally substituted by 1-3 radicals of amino, C1-C4 alkylamino, di-(C1-C4 alkyl)amino, C1-C5 alkanoyl amino, (C1-C4 alkoxy)carbonylamino, C1-C4 alkylsulfonyl amino, hydroxy, C1-C4 alkoxy, C1-C4 alkylthio, cyano, C1-C4 alkyl or C1-C4 haloalkyl of 1-3 halo radicals; or (3) aryl, heteroaryl, heterocyclyl or C3-C6 cycloalkyl radical optionally substituted by 1-3 radicals of amino, C1-C4 alkylamino, di-(C1-C4 alkyl)amino, C1-C5 alkanoylamino, (C1-C4 alkoxy)carbonylamino, C1-C4 alkylsulfonylamino, hydroxy, C1-C4 alkoxy, C1-C4 alkylthio, cyano, C1-C4 alkyl or C1-C4 haloalkyl of 1-3 halo radicals;
even more preferably, each R32 is independently (1) hydrogen radicals; (2) C1-C4 alkyl radical optionally substituted by phenyl or heteroaryl radical optionally substituted by 1-3 radicals of amino, C1-C4 alkylamino, di-(C1-C4 alkyl)amino, C1-C5 alkanoylamino, (C1-C4 alkoxy)carbonylamino, hydroxy, C1-C4 alkoxy, C1-C4 alkyl or trifluoromethyl radicals; or (3) phenyl or heteroaryl radical optionally substituted by 1-3 radicals of amino, C1-C4 alkylamino, di-(C1-C4 alkyl)amino, C1-C5 alkanoylamino, (C1-C4 alkoxy)carbonylamino, hydroxy, C1-C4 alkoxy, C1-C4 alkyl or trifluoromethyl radicals;
yet more preferably, each R32 is independently (1) hydrogen radicals; (2) C1-C4 alkyl radical or C1-C2 alkyl radical substituted by phenyl or heteroaryl radical optionally substituted by 1-3 radicals of amino, di-(C1-C2 alkyl)amino, acetamido, hydroxy, C1-C2 alkoxy, C1-C4 alkyl or trifluoromethyl radicals; or (3) phenyl or heteroaryl radical optionally substituted by 1-3 radicals of amino, di-(C1-C2 alkyl)amino, acetamido, hydroxy, C1-C2 alkoxy, C1-C4 alkyl or trifluoromethyl radicals;
still more preferably, each R32 is independently (1) hydrogen radicals; (2) C1-C4 alkyl radical or C1-C2 alkyl radical substituted by phenyl or heteroaryl radical optionally substituted by 1-3 radicals of amino, dimethylamino, acetamido, hydroxy, methoxy, methyl or trifluoromethyl radicals; or (3) phenyl or heteroaryl radical optionally substituted by 1-3 radicals of amino, dimethylamino, acetamido, hydroxy, methoxy, methyl or trifluoromethyl radicals; and
most preferably, each R32 is independently (1) hydrogen or C1-C4 alkyl radical; or (2) phenyl or heteroaryl radical optionally substituted by 1-2 radicals of amino, dimethylamino, acetamido, hydroxy, methoxy, methyl or trifluoromethyl radicals; and
each R33 is independently (1) hydrogen radical; or (2) alkyl radical optionally substituted by a radical of heterocyclyl, aryl or heteroaryl optionally substituted by 1-3 radicals of amino, alkylamino, dialkylamino, alkanoylamino, alkoxycarbonylamino, alkylsulfonylamino, hydroxy, alkoxy, alkylthio, cyano, alkyl or haloalkyl; preferably, each R33 is independently (1) hydrogen radical; or (2) C1-C4 alkyl radical optionally substituted by a radical of heterocyclyl, aryl or heteroaryl optionally substituted by 1-3 radicals of amino, C1-C4 alkylamino, di-(C1-C4 alkyl)amino, C1-C5 alkanoylamino, (C1-C4 alkoxy)carbonylamino, C1-C4 alkylsulfonylamino, hydroxy, C1-C4 alkoxy, C1-C4 alkylthio, cyano, C1-C4 alkyl or C1-C4 haloalkyl of 1-3 halo radicals; more preferably, each R33 is independently hydrogen or C1-C4 alkyl radical; and most preferably, each R33 is independently hydrogen or methyl radical.
Compounds of interest include the following:
3-(4-pyridyl)-2-(4-fluorophenyl)indole;
3-(4-fluorophenyl)-2-(4-pyridyl)indole;
6-amino-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole;
6-amino-3-(4-fluorophenyl)-2-(4-pyridyl)-7-aza-indole;
6-(4xe2x80x2-t-butoxycarbonylamino-1xe2x80x2-oxo-butylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole;
6-(4xe2x80x2-amino-1xe2x80x2-oxo-butylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole;
6-(5xe2x80x2-ureido-1xe2x80x2-oxo-2xe2x80x2-t-butoxycarbonylaminopentyl amino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole;
6-(5xe2x80x2-ureido-1xe2x80x2-oxo-2xe2x80x2-aminopentylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole;
6-(6xe2x80x2-t-butoxycarbonylamino-1xe2x80x2-oxo-2xe2x80x2-t-butoxycarbonyl aminohexylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole; 6-(6xe2x80x2-amino-1xe2x80x2-oxo-2xe2x80x2-aminohexylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole;
6-(5xe2x80x2-t-butoxycarbonylamino-1xe2x80x2-oxo-2xe2x80x2-t-butoxycarbonyl aminopentylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole;
6-(5xe2x80x2-amino-1xe2x80x2-oxo-2xe2x80x2-aminopentylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole;
6-(3xe2x80x2-(4-iodophenyl)-1xe2x80x2-oxo-2xe2x80x2-t-butoxycarbonylamino propylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole;
6-(3xe2x80x2-(4-iodophenyl)-1xe2x80x2-oxo-2xe2x80x2-aminopropylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole;
6-(3xe2x80x2-methyl-1xe2x80x2-oxo-2xe2x80x2-t-butoxycarbonylaminobutylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole;
6-(3xe2x80x2-methyl-1xe2x80x2-oxo-2xe2x80x2-aminobutylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole;
6-(3xe2x80x2-dimethyl-1xe2x80x2-oxo-2xe2x80x2-t-butoxycarbonylamino pentylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole;
6-(4xe2x80x2,4xe2x80x2-dimethyl-1xe2x80x2-oxo-2xe2x80x2-aminopentylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole;
6-(5xe2x80x2-t-butoxycarbonylamino-1xe2x80x2-oxo-pentylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole;
6-(5xe2x80x2-amino-1xe2x80x2-oxo-pentylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole;
6-(6xe2x80x2-t-butoxycarbonylamino-1xe2x80x2-oxo-hexylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole;
6-(6xe2x80x2-amino-1xe2x80x2-oxo-hexylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole;
6-(3xe2x80x2-cyclohexyl-1xe2x80x2-oxo-2xe2x80x2-t-butoxycarbonylaminopropyl amino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole;
6-(3xe2x80x2-cyclohexyl-1xe2x80x2-oxo-2xe2x80x2-aminopropylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole;
6-(4xe2x80x2-t-butoxycarbonyl-1xe2x80x2-oxo-2xe2x80x2-t-butoxycarbonylamino butylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole;
6-(4xe2x80x2-carboxy-1xe2x80x2-oxo-2xe2x80x2-aminobutylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole;
6-(3xe2x80x2-O-t-butoxy-1xe2x80x2-oxo-2xe2x80x2-t-butoxycarbonylaminobutyl amino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole;
6-(3xe2x80x2-hydroxy-1xe2x80x2-oxo-2xe2x80x2-aminobutylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole;
6-(3xe2x80x2-phenyl-1xe2x80x2-oxo-2xe2x80x2-t-butoxycarbonylaminopropyl amino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole;
6-(3xe2x80x2-phenyl-1xe2x80x2-oxo-2xe2x80x2-D,L-aminopropylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole;
6-(3xe2x80x2-(4-t-butoxyphenyl)-1xe2x80x2-oxo-2xe2x80x2-t-butoxycarbonylamino propylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole;
6-(3xe2x80x2-(4-hydroxyphenyl)-1xe2x80x2-oxo-2xe2x80x2-aminopropylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole;
6-(3xe2x80x2-t-butoxycarbonylamino-1xe2x80x2-oxo-propylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole;
6-(3xe2x80x2-amino-1xe2x80x2-oxo-propylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole;
6-(2xe2x80x2-t-butoxycarbonylamino-1xe2x80x2-oxo-ethylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole;
6-(2xe2x80x2-amino-1xe2x80x2-oxo-ethylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole;
6-(methylsulfonylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole;
6-(1xe2x80x2-oxo-ethylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole;
6-(2xe2x80x2-(5-chlorothienyl)sulfonylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole;
6-(phenylsulfonylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole;
6-(2xe2x80x2-N-phthaloyl-1xe2x80x2-oxo-ethylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole;
6-(3xe2x80x2-N-phthaloyl-1xe2x80x2-oxo-propylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole;
3-(4-pyridyl)-2-(4-fluorophenyl)-4,7-diaza-indole;
6-(2xe2x80x2-N-t-butoxycarbonyl-L-prolylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole;
6-(2xe2x80x2-L-prolylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole;
6-(2Sxe2x80x2-dimethylamino-1xe2x80x2-oxo-propylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole;
6-(2xe2x80x2-dimethylamino-1xe2x80x2-oxo-ethylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole;
6-(2xe2x80x2-N-methyl-t-butoxycarbonylamino-1xe2x80x2-oxo-ethylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole;
6-(2xe2x80x2-N-methyl-amino-1xe2x80x2-oxo-ethylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole;
6-(4xe2x80x2-N-t-butoxycarbonylisonipecotylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole;
6-(4xe2x80x2-isonipecotylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole;
6-(4xe2x80x2-methylsulfoxo-1xe2x80x2-oxo-2xe2x80x2S-t-butoxycarbonylamino butylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole;
6-(4xe2x80x2-methylsulfoxo-1xe2x80x2-oxo-2xe2x80x2S-aminobutylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole;
6-(3xe2x80x2-(3-pyridyl)-1xe2x80x2-oxo-2xe2x80x2S-t-butoxycarbonylaminopropyl amino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole;
6-(3xe2x80x2-(3-pyridyl)-1xe2x80x2-oxo-2xe2x80x2S-aminopropylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole;
6-(N,N-Di-t-butoxycarbonyl-L-histidinylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole;
6-(L-histidinylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole;
6-(N-t-butoxycarbonyl-3(S) 1xe2x80x2,2xe2x80x2,3xe2x80x2,4xe2x80x2-tetrahydro-3xe2x80x2-isoquinolinyloxo-amino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole;
6-(3(S) 1xe2x80x2,2xe2x80x2,3xe2x80x2,4xe2x80x2-tetrahydro-3xe2x80x2-isoquinolinyloxo amino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole;
6-(2xe2x80x2-phenyl-1xe2x80x2-oxo-2xe2x80x2R-N-t-butoxycarbonylaminoethyl amino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole;
6-(2xe2x80x2-phenyl-1xe2x80x2-oxo-2xe2x80x2R-aminoethylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole;
6-(2xe2x80x2-phenyl-1xe2x80x2-oxo-2xe2x80x2S-N-t-butoxycarbonylaminoethyl amino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole;
6-(2xe2x80x2-phenyl-1xe2x80x2-oxo-2xe2x80x2S-aminoethylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole;
6-(2xe2x80x2-phenyl-1xe2x80x2-oxo-2xe2x80x2R-N-t-butoxycarbonyl-N-methylamino ethylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole;
6-(2xe2x80x2-phenyl-1xe2x80x2-oxo-2xe2x80x2R-N-methylaminoethylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole;
6-(1xe2x80x2-oxo-2xe2x80x2S-t-butoxycarbonylaminopropylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole;
6-(1xe2x80x2-oxo-2xe2x80x2S-aminopropylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole;
6-(3xe2x80x2-phenyl-1xe2x80x2-oxo-2xe2x80x2-(L)-t-butoxycarbonylaminopropyl amino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole;
6-(3xe2x80x2-phenyl-1xe2x80x2-oxo-2xe2x80x2-(L)-aminopropylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole;
6-(1xe2x80x2-oxo-2xe2x80x2S-t-butoxycarbonyl-N-methylaminopropyl amino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole;
6-(1xe2x80x2-oxo-2xe2x80x2S-N-methylaminopropylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole;
6-(1xe2x80x2-oxo-2xe2x80x2S-t-butoxycarbonyl-N-methyl-4-methyl-2-amino pentyl-amino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole;
6-(1xe2x80x2-oxo-2xe2x80x2S-N-methyl-4-methyl-2-aminopentylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole;
6-(1xe2x80x2-oxo-2xe2x80x2R-t-butoxycarbonylaminopropylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole;
6-(1xe2x80x2-oxo-2xe2x80x2R-aminopropylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole;
6-(3xe2x80x2-(2-thienyl)-1xe2x80x2-oxo-2xe2x80x2-(L)-t-butoxycarbonylamino propylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole;
6-(3xe2x80x2-(2-thienyl)-1xe2x80x2-oxo-2xe2x80x2-(L)-aminopropylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole;
6-(3xe2x80x2-(4-azidophenyl)-1xe2x80x2-oxo-2xe2x80x2S-t-butoxycarbonylamino propylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole;
6-(3xe2x80x2-(4-azidophenyl)-1xe2x80x2-oxo-2xe2x80x2S-aminopropylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole;
6-(3xe2x80x2-(3-benzothienyl)-1xe2x80x2-oxo-2xe2x80x2S-t-butoxycarbonylamino propylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole;
6-(3xe2x80x2-(3-benzothienyl)-1xe2x80x2-oxo-2xe2x80x2S-aminopropylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole;
6-(4xe2x80x2-phenyl-1xe2x80x2-oxo-2xe2x80x2-(L)-t-butoxycarbonylaminobutyl amino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole;
6-(4xe2x80x2-phenyl-1xe2x80x2-oxo-2xe2x80x2-(L)-aminobutylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole;
6-(4xe2x80x2-phenyl-1xe2x80x2-oxo-2xe2x80x2-(D)-t-butoxycarbonylaminobutyl amino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole;
6-(4xe2x80x2-phenyl-1xe2x80x2-oxo-2xe2x80x2-(D)-aminobutylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole;
6-(2xe2x80x2-amino-1xe2x80x2-oxo-ethylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-1-isobutoxycarbonyl-7-aza-indole;
6-(phenylmethylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole;
6-(diethylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole;
6-(3xe2x80x2-phenylpropylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole;
6-(2xe2x80x2(R,S)-phenylpropylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole;
6-(2xe2x80x2(R,S)-ethylhexylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole;
6-Amino-5-chloro-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole;
6-Amino-5-fluoro-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole;
6-Amino-5-bromo-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole;
6-(di-isoamylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole;
6-(2xe2x80x2,2xe2x80x2-dimethylpropylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole;
6-(isoamylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole;
6-(2xe2x80x2-ethylbutylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole;
6-(2xe2x80x2-thienylmethylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole;
6-(3xe2x80x2,3xe2x80x2di-phenylpropylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole;
6-(ethylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole;
6-(3xe2x80x2-phenyl-1xe2x80x2-oxo-2xe2x80x2-(R,S)-methylpropylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole;
6-(2xe2x80x2-amino-1xe2x80x2-oxo-ethylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-1-methyl-7-aza-indole;
6-(3xe2x80x2,3xe2x80x2-dimethyl-1-oxo-butylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole;
6-(ethoxycarbonylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole;
6-(2xe2x80x2S-amino-1xe2x80x2-oxo-propylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-1-methyl-7-aza-indole;
6-(2xe2x80x2S-amino-1xe2x80x2-oxo-propylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-1-isobutyl-7-aza-indole; and
6-(2xe2x80x2S-amino-1xe2x80x2-oxo-propylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-1-cyclohexylmethyl-7-aza-indole.
As utilized herein, the following terms shall have the following meanings:
xe2x80x9cAlkylxe2x80x9d, alone or in combination, means a straight-chain or branched-chain alkyl radical containing preferably 1-15 carbon atoms (C1-C5), more preferably 1-8 carbon atoms (C1-C8), even more preferably 1-6 carbon atoms (C1-C6), yet more preferably 1-4 carbon atoms (C1-C4), still more preferably 1-3 carbon atoms (C1-C3), and most preferably 1-2 carbon atoms (C1-C2). Examples of such radicals include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, iso-amyl, hexyl, octyl and the like.
xe2x80x9cHydroxyalkylxe2x80x9d, alone or in combination, means an alkyl radical as defined above wherein at least one hydrogen radical is replaced with a hydroxyl radical, preferably 1-3 hydrogen radicals are replaced by hydroxyl radicals, more preferably 1-2 hydrogen radicals are replaced by hydroxyl radicals, and most preferably one hydrogen radical is replaced by a hydroxyl radical. Examples of such radicals include hydroxymethyl, 1-, 2-hydroxyethyl, 1-, 2-, 3-hydroxypropyl, 1,3-dihydroxy-2-propyl, 1,3-dihydroxybutyl, 1,2,3,4,5,6-hexahydroxy-2-hexyl and the like.
xe2x80x9cAlkenylxe2x80x9d, alone or in combination, means a straight-chain or branched-chain hydrocarbon radical having one or more double bonds, preferably 1-2 double bonds and more preferably one double bond, and containing preferably 2-15 carbon atoms (C2-C15), more preferably 2-8 carbon atoms (C2-C8), even more preferably 2-6 carbon atoms (C2-C6), yet more preferably 2-4 carbon atoms (C2-C4), and still more preferably 2-3 carbon atoms (C2-C3). Examples of such alkenyl radicals include ethenyl, propenyl, 2-methylpropenyl, 1,4-butadienyl and the like.
xe2x80x9cAlkynylxe2x80x9d, alone or in combination, means a straight-chain or branched chain hydrocarbon radical having one or more triple bonds, preferably 1-2 triple bonds and more preferably one triple bond, and containing preferably 2-15 carbon atoms (C2-C15), more preferably 2-8 carbon atoms (C2-C8), even more preferably 2-6 carbon atoms (C2-C6), yet more preferably 2-4 carbon atoms (C2-C4), and still more preferably 2-3 carbon atoms (C2-C3). Examples of such alkynyl radicals include ethynyl, propynyl (propargyl), butynyl and the like.
xe2x80x9cAlkoxyxe2x80x9d, alone or in combination, means a radical of the type xe2x80x9cRxe2x80x94Oxe2x80x94xe2x80x9d wherein xe2x80x9cRxe2x80x9d is an alkyl radical as defined above and xe2x80x9cOxe2x80x9d is an oxygen atom. Examples of such alkoxy radicals include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, iso-butoxy, sec-butoxy, tert-butoxy and the like.
xe2x80x9cAlkoxycarbonylxe2x80x9d, alone or in combination, means a radical of the type xe2x80x9cRxe2x80x94Oxe2x80x94C(O)xe2x80x94xe2x80x9d wherein xe2x80x9cRxe2x80x94Oxe2x80x94xe2x80x9d is an alkoxy radical as defined above and xe2x80x9cC(O)xe2x80x9d is a carbonyl radical.
xe2x80x9cAlkoxycarbonylaminoxe2x80x9d, alone or in combination, means a radical of the type xe2x80x9cRxe2x80x94Oxe2x80x94C(O)xe2x80x94NHxe2x80x94xe2x80x9d wherein xe2x80x9cRxe2x80x94Oxe2x80x94C(O)xe2x80x9d is an alkoxycarbonyl radical as defined above, wherein the amino radical may optionally be substituted, such as with alkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl and the like.
xe2x80x9cAlkylthioxe2x80x9d, alone or in combination, means a radical of the type xe2x80x9cRxe2x80x94Sxe2x80x94xe2x80x9d wherein xe2x80x9cRxe2x80x9d is an alkyl radical as defined above and xe2x80x9cSxe2x80x9d is a sulfur atom. Examples of such alkylthio radicals include methylthio, ethylthio, n-propylthio, isopropylthio, n-butylthio, iso-butylthio, sec-butylthio, tert-butylthio and the like.
xe2x80x9cAlkylsulfinylxe2x80x9d, alone or in combination, means a radical of the type xe2x80x9cRxe2x80x94S(O)xe2x80x94xe2x80x9d wherein xe2x80x9cRxe2x80x9d is an alkyl radical as defined above and xe2x80x9cS(O)xe2x80x9d is a mono-oxygenated sulfur atom. Examples of such alkylsulfinyl radicals include methylsulfinyl, ethylsulfinyl, n-propylsulfinyl, isopropylsulfinyl, n-butylsulfinyl, iso-butylsulfinyl, sec-butylsulfinyl, tert-butylsulfinyl and the like.
xe2x80x9cAlkylsulfonylxe2x80x9d, alone or in combination, means a radical of the type xe2x80x9cRxe2x80x94S(O)2xe2x80x94xe2x80x9d wherein xe2x80x9cRxe2x80x9d is an alkyl radical as defined above and xe2x80x9cS(O)2xe2x80x94xe2x80x9d is a di-oxygenated sulfur atom. Examples of such alkylsulfonyl radicals include methylsulfonyl, ethylsulfonyl, n-propylsulfonyl, isopropylsulfonyl, n-butylsulfonyl, iso-butylsulfonyl, sec-butylsulfonyl, tert-butylsulfonyl and the like.
xe2x80x9cAlkylsulfonylaminoxe2x80x9d, alone or in combination, means a radical of the type xe2x80x9cRxe2x80x94S(O)2xe2x80x94NHxe2x80x94xe2x80x9d wherein xe2x80x9cRxe2x80x94S(O)2xe2x80x94xe2x80x9d is an alkylsulfonyl radical as defined above, wherein the amino radical may optionally be substituted, such as with alkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl and the like.
xe2x80x9cArylxe2x80x9d, alone or in combination, means a phenyl or naphthyl radical which is optionally substituted with one or more substituents selected from alkyl, alkoxy, halogen, hydroxy, amino, azido, nitro, cyano, haloalkyl, carboxy, alkoxycarbonyl, cycloalkyl, heterocyclo, alkanoylamino, amido, amidino, alkoxycarbonylamino, N-alkylamidino, alkylamino, dialkylamino, N-alkylamido, N,N-dialkylamido, aralkoxycarbonylamino, alkylthio, alkylsulfinyl, alkylsulfonyl and the like. Examples of aryl radicals are phenyl, p-tolyl, 4-methoxyphenyl, 4-(tert-butoxy)phenyl, 3-methyl-4-methoxyphenyl, 4-CF3-phenyl, 4-fluorophenyl, 4-chlorophenyl, 3-nitrophenyl, 3-aminophenyl, 3-acetamidophenyl, 4-acetamidophenyl, 2-methyl-3-acetamidophenyl, 2-methyl-3-aminophenyl, 3-methyl-4-aminophenyl, 2-amino-3-methylphenyl, 2,4-dimethyl-3-aminophenyl, 4-hydroxyphenyl, 3-methyl-4-hydroxyphenyl, 1-naphthyl, 2-naphthyl, 3-amino-1-naphthyl, 2-methyl-3-amino-1-naphthyl, 6-amino-2-naphthyl, 4,6-dimethoxy-2-naphthyl, piperazinylphenyl and the like.
xe2x80x9cAralkylxe2x80x9d, alone or in combination, means an alkyl radical as defined above in which at least one hydrogen atom, preferably 1-2, is replaced by an aryl radical as defined above, such as benzyl, 1-, 2-phenylethyl, dibenzylmethyl, hydroxyphenylmethyl, methylphenylmethyl, diphenylmethyl, dichlorophenylmethyl, 4-methoxyphenylmethyl and the like.
xe2x80x9cAralkoxyxe2x80x9d, alone or in combination, means an alkoxy radical as defined above in which at least one hydrogen atom, preferably 1-2, is replaced by an aryl radical as defined above,. such as benzyloxy, 1-, 2-phenylethoxy, dibenzylmethoxy, hydroxyphenylmethoxy, methylphenylmethoxy, dichlorophenylmethoxy, 4-methoxyphenylmethoxy and the like.
xe2x80x9cAralkoxycarbonylxe2x80x9d, alone or in combination, means a radical of the type xe2x80x9cRxe2x80x94Oxe2x80x94C(O)xe2x80x94xe2x80x9d wherein xe2x80x9cRxe2x80x94Oxe2x80x94xe2x80x9d is an aralkoxy radical as defined above and xe2x80x9cxe2x80x94C(O)xe2x80x94xe2x80x9d is a carbonyl radical.
xe2x80x9cAryloxylxe2x80x9d, alone or in combination, means a radical of the type xe2x80x9cRxe2x80x94Oxe2x80x94xe2x80x9d wherein xe2x80x9cRxe2x80x9d is an aryl radical as defined above.
xe2x80x9cAlkanoylxe2x80x9d, alone or in combination, means a radical of the type xe2x80x9cRxe2x80x94C(O)xe2x80x94xe2x80x9d wherein xe2x80x9cRxe2x80x9d is an alkyl radical as defined above and xe2x80x9cxe2x80x94C(O)xe2x80x94xe2x80x9d is a carbonyl radical. Examples of such alkanoyl radicals include acetyl, trifluoroacetyl, hydroxyacetyl, propionyl, butyryl, valeryl, 4-methylvaleryl, and the like.
xe2x80x9cAlkanoylaminoxe2x80x9d, alone or in combination, means a radical of the type xe2x80x9cRxe2x80x94C(O)xe2x80x94NHxe2x80x94xe2x80x9d wherein xe2x80x9cRxe2x80x94C(O)xe2x80x94xe2x80x9d is an alkanoyl radical as defined above, wherein the amino radical may optionally be substituted, such as with alkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl and the like.
xe2x80x9cAminocarbonylxe2x80x9d, alone or in combination, means an amino substituted carbonyl (carbamoyl) radical, wherein the amino radical may optionally be mono- or di-substituted, such as with alkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, alkanoyl, alkoxycarbonyl, aralkoxycarbonyl and the like. xe2x80x9cAminocarbonylaminoxe2x80x9d, alone or in combination, means an amino substituted carbonyl substituted on a second amino (ureido) radical, wherein each amino radical may optionally be mono- or di-substituted, such as with alkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, alkanoyl, alkoxycarbonyl, aralkoxycarbonyl and the like.
xe2x80x9cAminoalkanoylxe2x80x9d, alone or in combination, means an alkanoyl radical as defined above derived in which at least one, preferably 1-2, hydrogen atom is replaced by an amino radical, wherein each amino radical may optionally be mono- or di-substituted, such as with alkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, alkanoyl, alkoxycarbonyl, aralkoxycarbonyl and the like.
xe2x80x9cBenzoxe2x80x9d, alone or in combination, means the divalent radical C6H4xe2x95x90 derived from benzene.
xe2x80x9cBicyclicxe2x80x9d as used herein is intended to include both fused ring systems, such as naphthyl and xcex2-carbolinyl, and substituted ring systems, such as biphenyl, phenylpyridyl, naphthyl and diphenylpiperazinyl.
xe2x80x9cCycloalkylxe2x80x9d, alone or in combination, means a saturated or partially saturated, preferably one double bond, monocyclic or bicyclic alkyl radical, preferably monocyclic, containing preferably 3-10 carbon atoms (C3-C10) more preferably 3-8 carbon atoms (C3-C8), even more preferably 3-6 carbon atoms (C3-C6), which is optionally be benzo fused and which is optionally substituted as defined herein with respect to the definition of aryl. Examples of such cycloalkyl radicals include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, dihydroxycyclohexyl, cycloheptyl, octahydronaphthyl, tetrahydronaphthyl, dimethoxytetrahydronaphthyl, 2,3-dihydro-1H-indenyl and the like.
xe2x80x9cCycloalkylalkylxe2x80x9d, alone or in combination, means an alkyl radical as defined above which is substituted by a cycloalkyl radical as defined above. Examples of such cycloalkylalkyl radicals include cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, 1-cyclopentylethyl, 1-cyclohexylethyl, 2-cyclopentylethyl, 2-cyclohexylethyl, hydroxycyclopentylpropyl, tetrahydronaphthylpropyl, cyclohexylbutyl and the like. xe2x80x9ccycloalkylcarbonylxe2x80x9d means an acyl radical of the formula cycloalkyl-C(O)xe2x80x94 in which the term xe2x80x9ccycloalkylxe2x80x9d has the significance give above, such as cyclopropylcarbonyl, cyclohexylcarbonyl, adamantylcarbonyl, 1,2,3,4-tetrahydro-2-naphthoyl, 2-acetamido-1,2,3,4-tetrahydro-2-naphthoyl, 1-hydroxy-1,2,3,4-tetrahydro-6-naphthoyl and the like.
xe2x80x9cHeteroatomsxe2x80x9d means nitrogen, oxygen and sulfur heteroatoms.
xe2x80x9cHeterocyclylxe2x80x9d, alone or in combination, means a saturated or partially unsaturated, preferably one double bond, monocyclic or bicyclic, preferably monocyclic, heterocycle radical containing at least one, preferably 1 to 4, more preferably 1 to 3, even more preferably 1-2, nitrogen, oxygen or sulfur atom ring member and having preferably 3-8 ring members in each ring, more preferably 5-8 ring members in each ring and even more preferably 5-6 ring members in each ring. xe2x80x9cHeterocyclylxe2x80x9d is intended to include sulfone and sulfoxide derivatives of sulfur ring members and N-oxides of tertiary nitrogen ring members, and carbocyclic fused, preferably 3-6 carbon atoms and more preferably 5-6 carbon atoms, and benzo fused ring systems. xe2x80x9cHeterocyclylxe2x80x9d radicals may optionally be substituted on at least one, preferably 1-4, more preferably 1-3, even more preferably 1-2, carbon atoms by halogen, alkyl, alkoxy, hydroxy, oxo, thioxo, aryl, aralkyl, heteroaryl, hetoroaralkyl, amidino, N-alkylamidino, alkoxycarbonylamino, alkylsulfonylamino and the like, and/or on a secondary nitrogen atom by hydroxy, alkyl, aralkoxycarbonyl, alkanoyl, alkoxycarbonyl, heteroaralkyl, aryl or aralkyl radicals. More preferably, xe2x80x9cheterocyclylxe2x80x9d, alone or in combination, is a radical of a monocyclic or bicyclic saturated heterocyclic ring system having 5-8 ring members per ring, wherein 1-3 ring members are oxygen, sulfur or nitrogen heteroatoms, which is optionally partially unsaturated or benzo-fused and optionally substituted by 1-2 oxo or thioxo radicals. Examples of such heterocyclyl radicals include pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiamorpholinyl, 4-benzyl-piperazin-1-yl, pyrimidinyl, tetrahydrofuryl, pyrazolidonyl, pyrazolinyl, pyridazinonyl, pyrrolidonyl, tetrahydrothienyl and its sulfoxide and sulfone derivatives, 2,3-dihydroindolyl, tetrahydroquinolinyl, 1,2,3,4-tetrahydroisoquinolinyl, 1,2,3,4-tetrahydro-1-oxo-isoquinolinyl, 2,3-dihydrobenzofuryl, benzopyranyl, methylenedioxyphenyl, ethylenedioxyphenyl and the like.
xe2x80x9cHeterocyclylalkylxe2x80x9d, alone or in combination, means an alkyl radical as defined above in which at least one hydrogen atom, preferably 1-2, is replaced by a heterocyclyl radical as defined above, such as pyrrolidinylmethyl, tetrahydrothienylmethyl, piperidinylethyl and the like.
xe2x80x9cHeteroarylxe2x80x9d, alone or in combination, means a monocyclic or bicyclic, preferably monocyclic, aromatic heterocycle radical, having at least one, preferably 1 to 4, more preferably 1 to 3, even more preferably 1-2, nitrogen, oxygen or sulfur atom ring member and having preferably 5-6 ring members in each ring, which is optionally benzo fused or saturated carbocyclic fused, preferably 3-4 carbon atoms (C3-C4) and which is optionally substituted as defined above with respect to the definitions of aryl and heterocyclyl. More preferably, xe2x80x9cheteroarylxe2x80x9d, alone or in combination, is a radical of a monocyclic or bicyclic aromatic heterocyclic ring system having 5-6 ring members per ring, wherein 1-3 ring members are oxygen, sulfur or nitrogen heteroatoms, which is optionally benzo-fused or saturated C3-C4-carbocyclic-fused. Examples of such heteroaryl groups include imidazolyl, 1-benzyloxycarbonylimidazol-4-yl, pyrrolyl, pyrazolyl, pyridyl, 2-(1-piperidinyl)pyridyl, 2-(4-benzyl piperazin-1-yl)-1-pyridinyl, pyrazinyl, triazolyl, furyl, thienyl, oxazolyl, thiazolyl, indolyl, quinolinyl, 1-oxido-2-quinolinyl, isoquinolinyl, 5,6,7,8-tetrahydroquinolyl, 5,6,7,8-tetrahydroisoquinolinyl, quinoxalinyl, benzothiazolyl, xcex2-carbolinyl, benzofuryl, benzimidazolyl, benzoxazolyl and the like.
xe2x80x9cHeteroaralkylxe2x80x9d, alone or in combination, means an alkyl radical as defined above in which at least one hydrogen atom, preferably 1-2, is replaced by a heteroaryl radical as defined above, such as 3-furylpropyl, 2-pyrrolyl propyl, chloroquinolinylmethyl, 2-thienylethyl, pyridylmethyl, 1-imidazolylethyl and the like.
xe2x80x9cHalogenxe2x80x9d and xe2x80x9chaloxe2x80x9d, alone or in combination, means fluoro, chloro, bromo or iodo radicals.
xe2x80x9cHaloalkylxe2x80x9d, alone or in combination, means an alkyl radical as defined above in which at least one hydrogen atom, preferably 1-3, is replaced by a halogen radical, more preferably fluoro or chloro radicals. Examples of such haloalkyl radicals include 1,1,1-trifluoroethyl, chloromethyl, 1-bromoethyl, fluoromethyl, difluoromethyl, trifluoromethyl, bis(trifluoromethyl)methyl and the like.
xe2x80x9cLeaving groupxe2x80x9d generally refers to groups readily displaceable by a nucleophile, such as an amine, a thiol or an alcohol nucleophile. Such leaving groups are well known in the art. Examples of such leaving groups include, but are not limited to, N-hydroxysuccinimide, N-hydroxybenzotriazole, halides, triflates, tosylates and the like. Preferred leaving groups are indicated herein where appropriate.
xe2x80x9cProtecting groupxe2x80x9d generally refers to groups well known in the art which are used to prevent selected reactive groups, such as carboxy, amino, hydroxy, mercapto and the like, from undergoing undesired reactions, such as nucleophilic, electrophilic, oxidation, reduction and the like. Preferred protecting groups are indicated herein where appropriate. Examples of amino protecting groups include, but are not limited to, aralkyl, substituted aralkyl, cycloalkenylalkyl and substituted cycloalkenyl alkyl, allyl, substituted allyl, acyl, alkoxycarbonyl, aralkoxycarbonyl, silyl and the like. Examples of aralkyl include, but are not limited to, benzyl, ortho-methylbenzyl, trityl and benzhydryl, which can be optionally substituted with halogen, alkyl, alkoxy, hydroxy, nitro, acylamino, acyl and the like, and salts, such as phosphonium and ammonium salts. Examples of aryl groups include phenyl, naphthyl, indanyl, anthracenyl, 9-(9-phenylfluorenyl), phenanthrenyl, durenyl and the like. Examples of cycloalkenylalkyl or substituted cycloalkylenylalkyl radicals, preferably have 6-10 carbon atoms, include, but are not limited to, cyclohexenyl methyl and the like. Suitable acyl, alkoxycarbonyl and aralkoxycarbonyl groups include benzyloxycarbonyl, t-butoxycarbonyl, iso-butoxycarbonyl, benzoyl, substituted benzoyl, butyryl, acetyl, tri-fluoroacetyl, tri-chloro acetyl, phthaloyl and the like. A mixture of protecting groups can be used to protect the same amino group, such as a primary amino group can be protected by both an aralkyl group and an aralkoxycarbonyl group. Amino protecting groups can also form a heterocyclic ring with the nitrogen to which they are attached, for example, 1,2-bis(methylene)benzene, phthalimidyl, succinimidyl, maleimidyl and the like and where these heterocyclic groups can further include adjoining aryl and cycloalkyl rings. In addition, the heterocyclic groups can be mono-, di- or tri-substituted, such as nitrophthalimidyl. Amino groups may also be protected against undesired reactions, such as oxidation, through the formation of an addition salt, such as hydrochloride, toluenesulfonic acid, trifluoroacetic acid and the like. Many of the amino protecting groups are also suitable for protecting carboxy, hydroxy and mercapto groups. For example, aralkyl groups. Alkyl groups are also sutiable groups for protecting hydroxy and mercapto groups, such as tert-butyl.
Silyl protecting groups are silicon atoms optionally substituted by one or more alkyl, aryl and aralkyl groups. Suitable silyl protecting groups include, but are not limited to, trimethylsilyl, triethylsilyl, tri-isopropylsilyl, tert-butyldimethylsilyl, dimethylphenylsilyl, 1,2-bis(dimethylsilyl)benzene, 1,2-bis(dimethylsilyl)ethane and diphenylmethylsilyl. Silylation of an amino groups provide mono- or di-silylamino groups. Silylation of aminoalcohol compounds can lead to a N,N,O-tri-silyl derivative. Removal of the silyl function from a silyl ether function is readily accomplished by treatment with, for example, a metal hydroxide or ammonium flouride reagent, either as a discrete reaction step or in situ during a reaction with the alcohol group. Suitable silylating agents are, for example, trimethylsilyl chloride, tert-buty-dimethylsilyl chloride, phenyldimethylsilyl chloride, diphenylmethyl silyl chloride or their combination products with imidazole or DMF. Methods for silylation of amines and removal of silyl protecting groups are well known to those skilled in the art. Methods of preparation of these amine derivatives from corresponding amino acids, amino acid amides or amino acid esters are also well known to those skilled in the art of organic chemistry including amino acid/amino acid ester or aminoalcohol chemistry.
Protecting groups are removed under conditions which will not affect the remaining portion of the molecule. These methods are well known in the art and include acid hydrolysis, hydrogenolysis and the like. A preferred method involves removal of a protecting group, such as removal of a benzyloxycarbonyl group by hydrogenolysis utilizing palladium on carbon in a suitable solvent system such as an alcohol, acetic acid, and the like or mixtures thereof. A t-butoxycarbonyl protecting group can be removed utilizing an inorganic or organic acid, such as HCl or trifluoroacetic acid, in a suitable solvent system, such as dioxane or methylene chloride. The resulting amino salt can readily be neutralized to yield the free amine. Carboxy protecting group, such as methyl, ethyl, benzyl, tert-butyl, 4-methoxyphenylmethyl and the like, can be removed under hydroylsis and hydrogenolysis conditions well known to those skilled in the art.
Procedures for preparing the compounds of this invention are set forth below. It should be noted that the general procedures are shown as it relates to preparation of compounds having unspecified stereochemistry. However, such procedures are generally applicable to those compounds of a specific stereochemistry, e.g., where the stereochemistry about a group is (S) or (R). In addition, the compounds having one stereochemistry (e.g., (R)) can often be utilized to produce those having opposite stereochemistry (i.e., (S)) using well-known methods, for example, by inversion.
The compounds of the present invention represented by Formula I above can be prepared utilizing the following general procedures as schematically shown in Schemes I and II. 
Several types of indole and azaindole synthesis can be used to prepare the compounds of this invention which are included by reference (for reviews of indole synthesis see G. Gribble Recent Developments in Indole Ring Synthesis-Methodology and Applications in Contemporary Organic Synthesis p-145-172; R. Sundberg and P. V. Nguyen Five Membered Ring Systems: Pyrroles and Benzo Derivatives, Chapter 5, Comprehensive Heterocyclic Chemistry) and the schemes shown below.
A general synthesis. of indoles and azaindoles useful for the preparation of the novel compounds of this invention is illustrated in Scheme I whereby an appropriately substituted acetylene (II) is coupled with an ortho iodoaniline (I) or a 1,2-iodoaminoheterocycle (for example, 2-amino-3-iodopyridine) using a palladium (0) mediated coupling under the conditions of Larock and coworkers (tetrabutylammonium chloride 1 eq., potassium acetate 5 eq., and triphenylphosphine (5 mol %), Tet. Lett. 1993, 2823-2826) to afford a mixture of regioisomeric indoles or azaindoles (III and IV) that can be separated by chromatography. Preferably, when utilizing the general synthesis of Scheme I in the preparation of the novel compounds of this invention, R1, R2, R3 and R4 will not contain halogen substituted aryl or heteroaryl and other radicals well known to those. skilled in the art which have the potential of interfering with, competing with or inhibiting the ring formation reaction.
A second general synthesis of indoles and azaindoles useful for the preparation of the novel compounds of this invention is illustrated in Scheme II whereby an appropriately substituted alpha-hydroxyketone (VI) or alpha-silyloxyketone (VIa) is coupled with an appropriately substituted aniline or amino substituted heterocycle (V) (for example, 2-aminopyridine, 3-aminopyridine, 4-aminopyridine, 3-amino-6-chloro pyridazine, 3-phenyl-6-aminopyridazine, 4-amino pyridazine, 3-methoxy-4-amino-6-chloropyridazine, 4-amino-2,6-dichloropyridine, 4-amino-2-chloropyridine, 4-amino-5-cyano-2-methoxy-pyridine, 4-amino-2-methyl pyridine, 4-amino-5-cyano-2-methoxypyridine, 2-amino-4-methylpyridine, 2-amino-4,6-dimethylpyridine, 2-amino-5- bromopyridine, 6-aminonicotinamide, 3-amino-2-chloro pyridine, 5-amino-2-chloropyridine, 5-amino-2-methoxy pyridine, 3-amino-2,6-dimethoxypyridine, 2,6-diamino pyridine, 2-aminopyrazine and 2,4-diamino pyrimidine, which are commercially available) under acid catalysis (in concentrated sulfuric acid at 190xc2x0 C. see: Herbert et al J. Chem. Soc. C 1969, p. 1505 or preferably under catalysis by p-toluenesulfonic acid in xylene with heat, see J. Szmuskovicz U.S. Pat. No. 3,565,912) to afford the regioisomeric indoles (III and IV) that can be separated by chromatography. Preferably, when utilizing the general synthesis of Scheme II in the preparation of the novel compounds of this invention, R1, R2, R3 and R4 will not contain an amino substituted aryl or heteroaryl and other radicals well known to those skilled in the art which have the potential of interfering with, competing with or inhibiting the ring formation reaction. The yields for the general reaction of Scheme II are more favorable when the substituted aniline or amino substituted heterocycle (V) is electron rich. Preferably, when R1, R2, R3 or R4 represent an electron withdrawing group directly attached to the aromatic ring, the electron withdrawing substituent should be introduced after the ring formation of Scheme II.
In a third general synthesis of indoles and azaindoles useful for the preparation of the novel compounds of this invention is illustrated in Scheme III whereby the appropriate grignard reagent is added to the cyano functional group of a 2-amino-1-cyanoaryl or heteroaryl (for example, 3-amino-4-cyanopyridine, 2-amino-5-nitrobenzonitrile, 2-amino-6-fluorobenzonitrile 
and 2-amino-5-chlorobenzonitrile, which are commercially available) system (VII) to afford the corresponding imine which upon hydrolysis affords the ketone (VIII). Alternatively, an ortho nitrobenzonitrile (for example, 2-methyl-6-nitrobenzonitrile, 5-chloro-2-nitrobenzonitrile, 4-cyano-3-nitrobenzotriflouride, 4,5-dimethoxy-2-nitrobenzonitrile, 4-chloro-2-nitrobenzonitrile, 6-nitro-o-anisonitrile and 6-bromo-2-cyano-4-nitroaniline, which are commercially available) can be converted into a 2-aminobenzonitrile as described by Jacini et al (Gazz. Chim. Ital. 1947, vol 77, 308). Acylation of the amino aryl or aminoheterocycle with the appropriate acid chloride (IX) (for example, benzoyl chloride, 3,5-bis(trifluoromethyl)benzoyl chloride, 2-bromobenzoyl chloride, 2-fluorobenzoyl chloride, pentafluorobenzoyl chloride 2,4-difluorobenzoyl chloride, 2,6-difluorobenzoyl chloride, 2,6-dichlorobenzoyl chloride, o-toluoyl chloride, m-anisoyl chloride, 3,4,5-trimethoxybenzoyl chloride, 4-biphenylcarbonyl chloride, 4-tert-butylbenzoyl chloride, 4-n-butylbenzoyl chloride, 4-cyanobenzoyl chloride, 2-naphthoyl chloride, 2,5-difluorobenzoyl chloride, 5-(dimethylsulfamoyl)-2-methoxybenzoyl chloride, 2,3-dichlorobenzoyl chloride, 1-naphthoyl chloride, 2-ethoxy-1-naphthoyl chloride and 2-naphthoyl chloride, which are commercially available) as shown in Scheme III affords the fused bicycle (III) after treatment with titanium (0) as described in the literature (Furstner et al Tet. Lett. 1991, 6695-6696). Such substituted benzoyl chlorides can be prepared from the corresponding commercially available benzoic acids by treatment with oxalyl chloride or thionyl chloride (Tet. Lett. 1993, 3543-3546; and Julia et al J. Chem. Soc. Perkin Trans. I 1991, Vol 5, 1101-1105, respectively). 
A general preparation of acetylenes for use in coupling in Scheme I is illustrated in Scheme IV. The appropriate aryl or heteroaryl aldehyde (XI) is reacted with diphenyl phosphite (XII) to afford the carbinol derivative (XIII) which is subsequently converted to the chloro derivative (XIV) by treatment with phosphorous oxychloride. Treatment of the chloromethanephosphonate with two equivalents of potassium t-butoxide followed by addition of the appropriate aldehyde (XV) affords the desired acetylene derivative (II) for use in Scheme I.
For purposes of illustration, examples of commercially available aryl aldehydes (XI) include 3-phenoxybenzaldehyde, 6-bromoveratraldehyde, 2-bromo benzaldehyde, 2-fluorobenzaldehyde, 4-fluoro benzaldehyde, 2-chlorobenzaldehyde, 2,4-dichloro benzaldehyde, 2-chloro-6-fluorobenzaldehyde, o-anisaldehyde, 2,3-dimethoxybenzaldehyde, 3-cyano benzaldehyde, 3-fluoro-p-anisaldehyde, 3-(3,4-dichlorophenoxy)benzaldehyde, 3-(3-(trifluoromethyl) phenoxy)benzaldehyde, 3-(4-methoxyphenoxy) benzaldehyde, 3-methyl-p-anisaldehyde, 4,4xe2x80x2-ethylbiphenyl-4-carboxaldehyde, 2-chloro-4-dimethylaminobenzaldehyde, 2,4,5-triethoxybenzaldehyde, 1-naphthaldehyde, 2-methoxy-1-naphthaldehyde, 4-methoxy-1 naphthaldehyde, 4-dimethylamino-1-naphthaldehyde, 4-methyl-1-naphthaldehyde, 2-benzyloxy-1-naphthaldehyde, 2-(2,4-dichlorobenzyloxy)-1-naphthaldehyde, 2-naphthaldehyde, 1-bromo-2-naphthaldehyde, 6-methoxy-2-naphthaldehyde and 7-methyl-2-naphthaldehyde.
For purposes of illustration, examples of commercially available heteroaryl aldehydes (XI) include 2,6-diphenyl-4-pyridinecarboxaldehyde, quinoline-3-carboxaldehyde, 2-chloro-3-quinolinecarboxaldehyde, 2-chloro-6-methoxy-3-quinolinecarboxaldehyde, 2-imidazolecarboxaldehyde, N-1-benzyl-2-imidazole carboxaldehyde, 2-methyl-3-imidazolecarboxaldehyde, 3-imidazolecarboxaldehyde, 2-ethyl-4-methyl-3-imidazolecarboxaldehyde, 4-methyl-5-imidazole carboxaldehyde and 2-phenyl-4-imidazolecarboxaldehyde.
Further, commercially available heteroaryl carboxylic acids or derivatives thereof can be converted to heteroaryl aldehydes by standard synthetic transformations well known to those skilled in the art. For example, heteroarylester can be reduced to the aldehyde by treatment with diisobutylaluminum hydride. For purposes of illustration, commercially available heteroaryl-carboxylic acids or derivatives thereof that can be converted into heteroaryl aldehydes (XI) include methyl 2-chloro-6-methyl-4-pyrimidinecarboxylate; 4-carboxypyrimidine; methyl 2,6-dimethylamino-4-pyrimidine carboxylate; and methyl 4,6-diphenyl-2-pyrimidine carboxylate. Alternatively, heteroaryl-halides can be converted into heteroaryl aldehydes (XI) by lithium-halogen exchange and quenching of the anion with dimethylformamide. For purposes of illustration, commercially available heteroarylhalides that can be converted into heteroaryl aldehydes (XI) include 6-chloro-2,4-dimethoxypyrimidine; 4-chloro-2-methylthio pyrimidine; 2-amino-4-chloro-6-methylpyrimidine; 4-chloro-2-phenylquinazoline; 4-chloro-2-methylquinoline; 4-chloro-2-methylquinoline; 4-chloro-7-(trifluoromethyl) quinoline; 4-chloro-6-methoxyquinoline; 4-chloro-2-picoline; 2,5-dimethyl-4-bromopyridine; 2-ethoxy-4-bromopyridine; 3-amino-4-chloroquinoline; and 3-amino-4-chloropyridine (note: the amino group of the substituted heteroaryl halide derivatives would first be suitably protected).
The alphahydroxyketone (VIa) or alphasilyloxyketone (VIb) of Scheme II can be prepared, for example when R11 is 4-pyridyl or 4-quinolinyl, by generating the anion of the protected silyl ether (XVI) and reacting it with the N-methyl-N-methoxyamide (XVII) as shown in Scheme Va (Gallagher et al Biorg. Med. Chem. Lett. 1995, 1171-1176). The N-methyl-N-methoxyamide (XVII) can be obtained through reaction of R12xe2x80x94C(O)Cl (for example, 3,5-bis(trifluoromethyl)benzoyl chloride; 2-bromobenzoyl chloride; 2-fluorobenzoyl chloride; pentafluorobenzoyl chloride; 2,4-difluorobenzoyl chloride; 2,6-difluoro benzoyl chloride; 2,6-dichlorobenzoyl chloride; o-toluoyl chloride; m-anisoyl chloride; 3,4,5-trimethoxy benzoyl chloride; 4-biphenylcarbonyl chloride; 4-tert-butyl benzoyl chloride; 4-n-butylbenzoyl chloride; 4-cyano benzoyl chloride; 2-naphthoyl chloride; 2,5-difluoro benzoyl chloride; 5-(dimethylsulfamoyl)-2-methoxybenzoyl chloride; 2,3-dichlorobenzoyl chloride; 1-naphthoyl chloride; 2-ethoxy-1-naphthoyl chloride; and 2-naphthoyl chloride, which are commercially available) with N,O-dimethylhydroxylamine in the presence of triethylamine. Such acid chlorides can be prepared from the corresponding R12xe2x80x94C(O)OH by treatment with oxalyl chloride or thionyl chloride (Tet. Lett. 1993, 3543-3546 and Julia et al J. Chem. Soc. Perkin Trans. I 1991, Vol 5, 1101-1105, respectively). 
Alternatively, the dimethylketal XX, prepared according to Scheme Vb, can be used in the process of Scheme II in place of the alphahydroxyketone (VIa) and alphasilyloxyketone (VIb). The dimethylketal XX can be prepared by reacting the anion of the dimethoxyacetal XIX with the aldehyde XV. The dimethoxyacetal XIX can be readily prepared from the corresponding aldehyde XI (for example, 2,6-diphenyl-4-pyridinecarboxaldehyde; quinoline-3-carboxaldehyde; 2-chloro-3-quinoline carboxaldehyde; 2-chloro-6-methoxy-3-quinoline carboxaldehyde; 2-imidazolecarboxaldehyde; N-1-benzyl-2-imidazolecarboxaldehyde; 2-methyl-3-imidazole carboxaldehyde; 3-imidazolecarboxaldehyde; 2-ethyl-4-methyl-3-imidazolecarboxaldehyde; 4-methyl-5-imidazole carboxaldehyde; and 2-phenyl-4-imidazolecarboxaldehyde, which are commercially available) using methods well know to those skilled in the art.
Alternatively, indoles or azaindoles (III) can be prepared (Scheme VI) by reacting 2-substituted indoles or azaindoles (XIX) (for example, 2-(4-fluorophenyl) indole; 2-(2-naphthyl)indole; and 2-(4-chlorophenyl) indole, which are commercially available) with R11xe2x80x94L, where L is a leaving group such as chloro, bromo, iodo, and the like radicals (for example, 4-chloropyridine, 4-chloroquinoline or 4-chloropyrimidine, which are commercially available). The 2-substituted indole or azaindole (XIX) can be treated with methyl magnesium bromide in ether followed by the addition of R11xe2x80x94L and heated in a metal bomb at 160xc2x0 C. for 20 hours to afford the indole or azaindole (III) (U.S. Pat. No. 3,551,567). 
The following is included to further illustrate synthetic procedures useful in the preparation of the novel compounds of this invention. A specific example of a palladium mediated coupling as described in Scheme I is illustrated in Scheme VII wherein 1-(4-pyridyl)-2-(4-fluorophenyl)ethyne (1) and 2-iodoaniline (2) affords the regioisomeric 2,3-disubstituted indoles (3) and (4) as a 1:4 mixture, respectively. Compound (4) can be separated from compound (3) via flash chromatography. 
Alternatively, substituted acetylenes and iodoanilines can be coupled via a palladium mediated process as described in Scheme I. Substituted 2-iodoanilines can either be purchased or prepared by standard methods well known to those skilled in the art. For instance, monoiodination of a substituted aniline derivative would afford the 2-iodoaniline derivative using a variety of iodination reagents, such as N-iodo succinimide. Substituted acetylenes can be obtained as described in Scheme IV as illustrated in Scheme VIII for 1-(4-pyridyl)-2-(4-fluorophenyl)ethyne (1). The adduct (6) of diphenylphosphite and 4-pyridinecarboxaldehyde (5) is treated with phosphorous oxychloride to afford the chloro derivative (7). Condensation and elimination to the alkyne (1) is effected by treating the chloro derivative (7) and 4-fluorobenzaldehyde (8) with 2.1 equivalents of potassium t-butoxide. 
Scheme IX illustrates the preparation of substituted indoles according to the method of Scheme III, a titanium oxide mediated coupling. The grignard of 4-bromopyridine (10) is prepared by low temperature treatment (xe2x88x9278xc2x0 C.) with n-butyl lithium followed by treatment with magnesium bromide etherate. A cooled solution of the grignard of (10) is added to anthranilonitrile (9) at low temperature (xe2x88x9250xc2x0 C.) followed by warming to room temperature. The resultant imine (11) is hydrolyzed by treatment with sulfuric acid to the anilinoketone (12). Acylation of the anilinoketone (12) with 4-fluorobenzoyl chloride (13) affords the ketoamide (14). The regiospecific synthesis of indole (3) is completed by treatment of the ketoamide (14) with titanium oxide. 
Scheme X illustrates the preparation of indoles and azaindoles according to the method of Scheme II, acid mediated condensation of an aminoaryl or aminoheteroaryl and a substituted benzoin. Condensation of 2,6-diaminopyridine (15) with 1-(4-fluorophenyl)-2-t-butyldimethylsiloxy-2-(4-pyridyl)ethanone (16) is effected by treatment with an excess of p-toluenesulfonic acid in xylene at high temperatures to afford the azaindoles (17) and (18) which can be separated by flash chromatography.
Further fuctionalization of the 2,3-disubstituted indoles or azaindoles can be readily accomplished by reaction at an appropriately positioned group, such as an amino, carboxy, halo, substituted alkyl and the like group, on the 2,3-disubstituted indoles or azaindoles. Scheme XI illustrates functionalizing a 6-amino derivative (17) of a 2,3-disubstituted azaindole. Reaction of the 6-amino group of (17) with the mixed anhydride of N-4-t-butoxycarbonylaminobutyric acid (20) affords the N-4-t-butoxycarbonylaminobutanoyl compound (21), which can be readily converted into. the aminobutanoyl compound (22) by exposure to 90% trifluoroacetic acid and water for 1 hour. Similarly, the aminoalkylsulfonyl compound (26) can be prepared according to the method shown in Scheme XII. 
Further functionalization of 2,3-disubstituted indoles or azaindoles can be readily accomplished by site specific electrophilic substitution, and subsequent elaboration at the point of attachment of a newly introduced electrophile. For example, in Scheme XIII, N-bromosuccinimide (NBS) is reacted with compound (17) to introduce a bromo radical at the 5-position of (17) affording the bromo derivative (27). The bromo compound (27) can also be used to introduce other substituents at the 5-position using methods and reagents well known to those skilled in the art. Similarly, a fluoro radical can be introduced at the 5-position of (17) through the use of N-fluorobenzenesulfonimide to afford the fluoro derivative (28). Alternatively, a bromo compound like (27), or an appropriately 6-amino and indole NH protected derivative thereof, can be converted into the fluoro derivative by lithium halogen exchange followed by quenching of the lithio anion with N-fluorobenzene sulfonimide (Synlett. 187 (1991) and Tetrahedron Lett. 1631 (1992)). These reactions exemplify in a specific fashion the further substitution of an azaindole system after the indole has been formed by electrophilic substitution. In a more general sense, they demonstrate how other electrophilic agents (for example, iodine, Vilsmeier reagent, nitric acid and the like) can be used to substitute azaindoles and indoles in a specific fashion. 
Further, functionalization of 2,3-disubstituted indoles or azaindoles can be readily accomplished at the indole nitrogen by utilizing the conditions of Mitsunobu wherein an appropriate alcohol is activated by treatment with triphenylphosphine and diethylazodicarboxylate (DEAD) and then reacted with the indole or azaindole compound. For example, in Scheme XV, the indole nitrogen of (29) is N-methylated under the Mitsunobu conditions and then reacted with NBS to afford the 5-bromo-N-1-methylderivative followed by deprotection affording (32). 
Further, functionalization of 2,3-disubstituted indoles or azaindoles can be readily accomplished by site specific electrophilic halogenation followed by palladium mediated coupling to introduce aryl substituent. Alternatively, an aryl halide can be converted into an aryl stannane by lithium halogen exchange followed by quenching with a trialkylstannyl chloride (for example, tributylstannyl chloride or trimethylstannyl chloride). The aryl stannane can then be reacted in the presence of palladium (O) in a coupling process. Those skilled in the art are well versed in the diverse conditions and methods available for palladium (O) assisted couplings (Palladium Reagents and Catalystsxe2x80x94Innovations in Organic Synthesis by Jiro Tsuji, Wiley (1995); and Palladium Reagents in Organic Syntheses by Heck, Academic Press (1985)). 
Schemes XVI-XXIII illustrate the use of palladium mediated couplings to prepare compounds of this invention. For example, bromo compound (31) can be coupled to aniline (other amines work as well, see Buchwald et al., J. Am. Chem. Soc. 7901 (1994); Buchwaid et al., Angew. Chem. Int. Ed. Engl. 1348 (1995); Hartwig et al., J. Am. Chem. Soc. 5969 (1994)) in a palladium (0) mediated coupling to afford compound (33) as illustrated in Scheme XVI. Alternatively, compound (31) can be coupled with an aryl boronic acid to afford a phenyl substituted derivative (43) as illustrated in Scheme XVII 
(see Chem. Lett. 1405 (1989); Bull. Chem. Soc. Jpn 3008 (1988); Synthesis 184 (1989); Tetrahedron Lett 1523 (1990)). Bromo compound (34) can be coupled to a heterocycle like imidazole as exemplified in Scheme XVIII which has been demonstrated in the literature for similar systems ((35) plus 2-bromopyridine using tetrakistriphenylphosphine palladium (O), A. S. Bell et al., Tetrahedron Lett. 5013 (1988) and Synthesis 843 (1987)). Compound (37) (Scheme IXX) can be prepared from 4-amino-2-mercapto-6-methylpyrimidine by conversion to the corresponding 2-iodo derivative (iodine and hydrogen iodide in analogy to the conditions of bromine and HBr found in Zh. Org. Khim. (1991) 2235-2236) then converted into (37) in the manner illustrated in Scheme X. The Reformatsky reagent (38) can be coupled to the iodo derivative (37) using tetrakistriphenylphosphine 
palladium (0) as in a similar manner to the previously described coupling with 4,6-dimethyl-2-iodopyrimidine (see: Yamanaka et al., Chem. Pharm. Bull. 4309 (1985)). An unnatural amino acid can be prepared directly from compound (41) of Scheme XX by reduction (for example, hydrogen gas in the presence of Rh(DIPAMP)). Compound (41) itself can be obtained through a palladium (O) mediated coupling of eneamide (40) directly with bromo derivative (41) utilizing the previously employed conditions for similar transformations (Pd2(dba)3, (o-tol)3P, Et3N, acetonitrile, see J Org. Chem. 2584 (1991); Synthesis 414 (1989); J. Org. Chem. 1289 (1991); Tetrahedron 7151 (1990)). The bromo derivative (31) can be converted to the carboxymethyl derivative (42) as illustrated in Scheme XXI utilizing the previously employed conditions for similar transformations (Pd2(dba)3, triphenylphosphine, methanol, carbon monoxide used with 2,6-dichloropyrazine, see Synthesis 923 (1990)). An acetylenic group can be directly coupled to the azaindole or indole as illustrated in Scheme XXII utilizing the previously employed conditions for similar transformations (tetrakistriphenylphosphine palladium (O), CuI, Et3N xe2x80x94see: Synthesis 728 (1984)). Compound (44) can be obtained utilizing commercially available 3-methoxy-4-amino-6-chloro-pyridazine in the manner of Scheme X. Vinyl functionalization of the appropriate 2,3-disubstituted indoles or azaindoles can be readily 
accomplished as illustrated in Scheme XXIII. Conversion of the bromo derivative (47) of Scheme XXIII to the tributyl stannyl derivative as described above can be followed by a palladium (0) mediated coupling to a vinyl triflate utilizing the previously employed conditions for similar transformations (Pd2(dba)3, Ph3As, NMP, see Tetrahedron Lett. 4243 (1991)). Compound (47) can be obtained from 3-amino-2-bromoaniline in a similar manner to Scheme X. 
Further functionalization of the appropriate 2,3-disubstituted indoles or azaindoles can be readily accomplished by introduction of a sulfide group as illustrated in Scheme XXIV or alternatively the thiol can be introduced prior to indole formation. Examples of thiol introduction include alkyl thiol (Rumler et al., Pharmazie (1990) 657-659) and thiol itself (Pascual et al., Bull. Soc. Chim. Belg. 101:297-302 (1992)). For example, the chlorogroup of compound (50) can be displaced by a thiol reagent. The sulfide (51) can be oxidized to the sulfoxide (52) by treatment with t-butylhydroperoxide in the presence of the pyridine (Kagan et al., Tetrahedron asymmetry (1990) 597-610) or further oxidized to the sulfone (53) (Trost et al., Tetrahedron Lett (1981) 1287).
A sulfonamide radical can be introduced prior to the indole forming process (Schemes I or II) and then further fuctionalized as illustrated in Scheme XXV. Reaction of the sulfonamide (56) with excess chloroformates results in formation of compound (57) wherein CR3=xe2x80x94S(O)2xe2x80x94NR22xe2x80x94C(O)xe2x80x94OR20 (J. Med. Chem. (1990) 2393-2407). Reaction of. the sulfonamide (56) with acid chlorides after deprotonation of the sulfonamide with sodium hydride results in formation of compound (58) wherein CR3=xe2x80x94S(O)2xe2x80x94NR22xe2x80x94C(O)xe2x80x94R21 (Curran, J. Org. Chem. (1990) 4584-4595). Reaction of the sulfonamide (56) with isocyanates results in the formation of compound (59) wherein CR3=xe2x80x94S(O)2xe2x80x94NR22xe2x80x94C(O)xe2x80x94NR5R21 where R5=hydrogen (Howbert et al., J. Med. Chem. (1990) 2393-2407).
Introduction of the substituent CR3=xe2x80x94NR22xe2x80x94S(O)2xe2x80x94NR5R21 can be accomplished as illustrated in Scheme XXVI. First, the amino group of compound (60) can be alkylated in a reductive amination to afford compound (61). Then the alkylated amino substituent of compound (61) can be reacted with o-phenylene sulfate to afford (62) followed by further reaction with a second amine as illustrated in Scheme XXVI to afford compound (63) wherein CR3=xe2x80x94NR22xe2x80x94S(O)2xe2x80x94NR5R21 (Lee et al., Bull. Korean Chem. Soc. (1992), 357).
Additional methods of indole and azaindole preparation are included by reference: G. Gribble Recent Developments in Indole Ring Synthesis-Methodology and Applications in Contemporary Organic Synthesis p-145-172; R. Sundberg and P. V. Nguyen Five Membered Ring Systems: Pyrroles and Benzo Derivatives, Chapter 5, Comprehensive Heterocyclic Chemistry. It will be understood that these novel compounds are not limited to the disclosed methods of making them.
Sulfonyl halides can be prepared by the reaction of a suitable alkyl, aryl, heteroaryl, heterocyclyl and the like Grignard or lithium reagents with sulfuryl chloride, or sulfur dioxide followed by oxidation with a halogen, preferably chlorine. Alkyl, aryl, heteroaryl, heterocyclyl and the like Grignard or lithium reagents can be prepared from their corresponding halide (such as chloro or bromo) compounds which are commercially available or readily prepared from commercially available starting materials using known methods in the art. Alternatively, mercaptans may be oxidized to sulfonyl chlorides using chlorine in the presence of water under carefully controlled conditions. Additionally, sulfonic acids may be converted into sulfonyl halides using reagents such as PCl, SOCl2, ClC(O)C(O)Cl and the like, and also to anhydrides using suitable dehydrating reagents. The sulfonic acids are either commercially available or may be prepared using procedures well known in the art from commercially available starting materials. In place of the sulfonyl halides, sulfinyl halides or sulfenyl halides can be utilized to prepare compounds wherein the sulfonyl moiety is replaced by an sulfinyl or thio moiety, respectively. Arylsulfonic acids, benzo fused heterocyclyl sulfonic acids or heteroaryl sulfonic acids can be prepared by sulfonation of the aromatic ring by well known methods in the art, such as by reaction with sulfuric acid, SO3, SO3 complexes, such as DMF(SO3), pyridine(SO3), N,N-dimethylacetamide(SO3), and the like. Preferably, such sulfonyl halides are prepared from such aromatic compounds by reaction with DMF(SO3) and SOCl2 or ClC(O)C(O)Cl. The reactions may be performed stepwise or in a single pot.
Alkyl sulfonic acids, aryl sulfonic acids, heterocyclyl sulfonic acids, heteroaryl sulfonic acids, alkylmercaptans, arylmercaptans, heterocyclylmercaptans, heteroarylmercaptans, alkylhalides, arylhalides, heterocyclylhalides, heteroarylhalides, and the like are commercially available or can be readily prepared from starting materials commercially available using standard methods well known in the art.
Thioether derivatives can be converted into the corresponding sulfone or sulfoxide by oxidizing the thioether derivative with a suitable oxidation agent in a suitable solvent. Suitable oxidation agents include, for example, hydrogen peroxide, sodium meta-perborate, oxone (potassium peroxy monosulfate), meta-chloroperoxybenzoic acid, periodic acid and the like, including mixtures thereof. Suitable solvents include acetic acid (for sodium meta-perborate) and, for other peracids, ethers such as THF and dioxane, and acetonitrile, DMF and the like, including mixtures thereof.
The chemical reactions described above are generally disclosed in terms of their broadest application to the preparation of the compounds of this invention. Occasionally, the reactions may not be applicable as described to each compound included within the disclosed scope. The compounds for which this occurs will be readily recognized by those skilled in the art. In all such cases, either the reactions can be successfully performed by conventional modifications known to those skilled in the art, e.g., by appropriate protection of interfering groups, by changing to alternative conventional reagents, by routine modification of reaction conditions, and the like, or other reactions disclosed herein or otherwise conventional, will be applicable to the preparation of the corresponding compounds of this invention. In all preparative methods, all starting materials are known or readily prepared from known starting materials.
Prodrugs of the compounds of this invention are also contemplated by this invention. A prodrug is an active or inactive compound that is modified chemically through in vivo physicological action, such as hydrolysis, metabolism and the like, into a compound of this invention following administration of the prodrug to a patient. The suitability and techniques involved in making and using prodrugs are well known by those skilled in the art. For a general discussion of prodrugs involving esters see Svensson and Tunek Drug Metabolism Reviews 165 (1988) and Bundgaard Design of Prodrugs, Elsevier (1985). Examples of a masked carboxylate anion include a variety of esters, such as alkyl (for example, methyl, ethyl), cycloalkyl (for example, cyclohexyl), aralkyl (for example, benzyl, p-methoxybenzyl), and alkylcarbonyloxyalkyl (for example, pivaloyloxymethyl). Amines have been masked as arylcarbonyloxymethyl substituted derivatives which are cleaved by esterases in vivo releasing the free drug and formaldehyde (Bungaard J. Med. Chem. 2503 (1989)). Also, drugs containing an acidic NH group, such as imidazole, imide, indole and the like, have been masked with N-acyloxymethyl groups (Bundgaard Design of Prodrugs, Elsevier (1985)). Hydroxy groups have been masked as esters and ethers.
Without further elaboration, it is believed that one skilled in the art can, using the preceding description, utilize the present invention to its fullest extent. The following preferred specific embodiments are, therefore, to be construed as merely illustrative, and not limitative of the remainder of the disclosure in any way whatsoever.
All reagents were used as received without purification. All proton and carbon NMR spectra were obtained on either a Varian VXR-300 or VXR-400 nuclear magnetic resonance spectrometer.